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15 October 2026, Volume 21 Issue 10 Previous Issue   

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Extracellular matrix remodeling therapeutic strategies to tackle central nervous system diseases Daniel A. Domingo-Lopez, Maria Rosa Aguilar de Armas, Sergio Martin-Saldaña 2026, 21 (10):  4485-4494.  doi: 10.4103/NRR.NRR-D-25-01562 Abstract ( 44 )   PDF (6347KB) ( 11 )   Save Neurodegenerative diseases are a global burden due to the increased life expectancy. Neuroinflammation is not only a result of neurodegeneration but a key player in the initiation and onset of it. Due to the inherent complexity of these diseases, there is a need for the development of better treatments, as well as the discovery of new therapeutic targets. In this sense, knowledge about extracellular matrix remodeling after injury in the central nervous system was overseen for a century, but it has blossomed in the last three decades. Nowadays, we possess strong evidence regarding the imbalance, over-synthesis, and changes in the organization of most key components of the extracellular matrix after neuroinflammation and neurodegeneration. Thus, hyaluronic acid, chondroitin sulphate proteoglycans, or fibronectin presented an impairment in their anabolism and catabolism, which could be a cause or a consequence of the inflammatory and degenerative process. Regardless, it is clear that extracellular matrix remodeling plays a pivotal role in the onset and resolution of inflammation-driven neurological disorders by creating a non-permissive niche for self-restoration of the neural homeostasis. Despite being an emerging area of study, extracellular matrix changes have been explored in the last decades in the central nervous system to shed light on their potential as diagnostic markers as well as therapeutic targets. The extracellular matrix fingerprint in diseases such as multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, or stroke has been described both in preclinical models and in post-mortem clinical samples. Herein, we provided an overview of the state of the art of extracellular matrix components and function in the central nervous system, both under homeostasis and in neurodegeneration. Then, we critically revise the therapeutic efforts targeting the extracellular matrix, aiming to tackle neurodegenerative disorders. Altogether, this review contextualizes the current understanding of extracellular matrix in the central nervous system and its remodeling after neuroinflammation, its role in disease onset and resolution, and how this knowledge is being applied to the development of new therapeutic approaches. Related Articles | Metrics

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Stem cell derived neural organoids approaches for neurological diseases Rosalie Elvira, Xiao-Xue Dong, Alfred Sun Xuyang, Wai Hon Chooi, Huck Hui Ng, Hongyan Wang, Yun-Cheng Wu, Eng King Tan, Zhi Dong Zhou 2026, 21 (10):  4495-4505.  doi: 10.4103/NRR.NRR-D-25-01004 Abstract ( 37 )   PDF (5025KB) ( 4 )   Save Traditional two-dimensional cultures and animal models often fall short in capturing the complexities of neurodevelopmental and neurodegenerative diseases. However, recently developed neural organoid approaches, three-dimensional structures derived from human pluripotent stem cells, have become powerful tools for modeling human neuronal development and disease. Unlike traditional models, neural organoids provide significant insights and improved modeling capabilities. Here, we explore various types of neural organoids in disease modeling and outline distinct protocols for generating each type, including specific patterning methods, growth factors, and differentiation durations. The potential and advantages of co-culturing neural organoids with other cells and tissues are also discussed. While neural organoids have already made significant contributions to neuroscience research, future directions should focus on enhancing their maturation and functionality. The progression of neural organoids approaches will generate more accurate and comprehensive disease models, ultimately adding to our understanding of disease pathogenesis and paving the way for future precision therapies for neurological diseases. Related Articles | Metrics

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Functional near-infrared spectroscopy: Systematic mapping of abnormal brain function features in neurological disorders Yunjie Li, Yangyang Feng, Xia Liu, Ruochao Yuan, Shiling Chen, Jingyi Wang, Chao Pan, Gaigai Li, Zhouping Tang 2026, 21 (10):  4506-4522.  doi: 10.4103/NRR.NRR-D-25-00595 Abstract ( 34 )   PDF (2654KB) ( 3 )   Save Functional near-infrared spectroscopy quantifies cerebral hemodynamic signals by capturing oxygenation-dependent changes in hemoglobin in a noninvasive, portable, and ecologically valid manner, providing a unique insight into neurovascular coupling. However, functional imaging biomarkers with high ecological validity for neurological disorders such as stroke, Parkinson’s disease, dementia, amyotrophic lateral sclerosis, epilepsy, spinal cord injury, and traumatic brain injury are lacking, limiting the mechanistic understanding, treatment evaluations, and individualized interventions. The aim of this review is to systematically summarize evidence from the past decade on the use of functional near-infrared spectroscopy under the aforementioned conditions, synthesize its value for revealing neural mechanisms and assessing therapeutic responses, and identify current technical bottlenecks and future directions for advancement. Collectively, the findings demonstrate that functional near-infrared spectroscopy possesses substantial and far-reaching potential for uncovering the neural mechanisms underlying disease and for evaluating treatment-induced changes in brain function. Equipped with wearable probes, functional near-infrared spectroscopy can continuously and noninvasively monitor brain activity in naturalistic environments for extended periods, thereby overcoming the limitations of conventional imaging modalities that can only acquire data under restricted settings. This capability can furnish unprecedented objective neuroimaging evidence for neuroregenerative therapy research. Moreover, the portability of functional near-infrared spectroscopy allows it to be integrated into neurofeedback training systems: hemoglobin signals can be fed back to participants within milliseconds, enabling targeted, individualized, closed-loop modulation of brain function and considerably expanding the scope of hemodynamics-based neurofeedback. When combined with other brain function assays (such as electroencephalography) and intervention techniques (such as transcranial magnetic stimulation and transcranial direct current stimulation), functional near-infrared spectroscopy also supplies high-temporal-resolution hemodynamic information, laying a critical foundation for the construction of high-precision noninvasive brain–computer interfaces, real-time cognitive-state decoding, and adaptive neuromodulation. Admittedly, almost all existing functional near-infrared spectroscopy studies are still observational and have small sample sizes, short follow-ups, and insufficient controls—shortcomings that together produce low-grade evidence. Therefore, there is still a significant gap before clinical translation can be achieved. Technically, the limited penetration depth of functional near-infrared spectroscopy restricts sampling to the superficial cortex, leaving deep nuclei largely unreachable. In addition, no consensus exists across devices regarding optode layout, light-source choice, motion-artifact correction, or analytical pipelines, creating pronounced heterogeneity that undermines reproducibility. With artificial intelligence and big data analytics advancing rapidly, functional near-infrared spectroscopy embedded within multimodal fusion frameworks is now poised to systematically map aberrant brain function signatures of neurological disorders, identify pathological regions suitable for targeted intervention, and provide real-time assessments of functional changes produced by neuroregenerative therapies.  Related Articles | Metrics

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Increased oxygen demand during exercise as a stimulus for neuroprotection: A working hypothesis Johannes Burtscher, Robert Motl, Erich Hohenauer, Luis Santos, Atbin Djamshidian, Hannelore Ehrenreich, Florian Krismer, Klaus Berek, Martin Burtscher, Katharina Hüfner, Martin Kopp 2026, 21 (10):  4523-4528.  doi: 10.4103/NRR.NRR-D-25-00864 Abstract ( 56 )   PDF (1851KB) ( 0 )   Save Aerobic (endurance) exercise training protects from age-related neurological and psychiatric diseases. The bidirectional signaling between tissues directly involved in aerobic exercise, such as skeletal muscle and the brain, is well established; however, the precise mechanisms by which exercise benefits the brain remain elusive. We summarize the role of hypoxia (reduced oxygen availability) signaling as a potential mediator of exercise outcomes on the brain. The increased oxygen demand in organs such as skeletal muscle and heart during aerobic exercise induces hypoxia responses, including the activation of hypoxia-inducible factor pathways. These responses promote adaptations leading to improved oxygen transport, mitochondrial functions, and oxidative stress management in the brain and thereby counteract central pathological developments associated with neuropsychiatric and neurodegenerative diseases. Passive hypoxia exposures can similarly improve brain functions; we provide an extensive overview of the existent literature on that topic. We conclude that the combination of aerobic exercise and ambient hypoxia can result in synergistic and/or additive positive outcomes in the brain. However, the dose of either stimulus and individual resilience/vulnerabilities determines if the induced stress responses are successful and safe. If the stress management capacities are insufficient, the different stimuli may have antagonistic effects or inhibit beneficial adaptations. The selection of combinations for optimal adaptation is an important challenge for future research. Related Articles | Metrics

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Brain organoids as models of extracellular vesicle–mediated human neural communication Giuliana La Rosa, Erika Pascale, Maria Roberta Iazzetta, Edoardo Sozzi, Annalisa Fico, Elvira Immacolata Parrotta, Alessandro Fiorenzano 2026, 21 (10):  4529-4537.  doi: 10.4103/NRR.NRR-D-25-01806 Abstract ( 28 )   PDF (8367KB) ( 0 )   Save Cellular communication orchestrates human brain development through complex interactions involving adhesion molecules, signaling ligands, extracellular matrix, and extracellular vesicles. While intrinsic genetic programs governing neural differentiation are well characterized, the roles of extrinsic, non-cell-autonomous signaling, particularly extracellular-mediated communication, remain poorly understood. Here, we review recent advances in three-dimensional brain organoids derived from human pluripotent stem cells as physiologically relevant models that recapitulate key aspects of human neurodevelopment, enabling detailed study of extracellular vesicle-mediated intracellular signaling. We highlight how organoid systems facilitate the investigation of extracellular vesicle cargo dynamics and their influence on neural cell fate, migration, and circuit assembly, as well as their involvement in neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. These insights show the potential of brain organoids to unravel complex cellular interactions and inform biomarkers discovery and therapeutic strategies for neurological diseases.  Related Articles | Metrics

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CD11c+ microglia: From basic research to clinical application Zipeng Zhou, Yongfei Zhao, Xiangyi Fan, Jinhui Zhang, Ruihan Niu, Yifei Ma, Fei Xie, Peifu Tang, Xifan Mei, Licheng Zhang, Junhao Deng 2026, 21 (10):  4538-4549.  doi: 10.4103/NRR.NRR-D-25-00868 Abstract ( 42 )   PDF (2611KB) ( 1 )   Save CD11c+ microglia are a functionally specialized subpopulation of microglia that play a crucial role in the pathophysiological processes of various central nervous system diseases. This review synthesizes compelling evidence that CD11c+ microglia exhibit unique transcriptomic and phagocytic characteristics. These characteristics distinguish them from homeostatic microglia and support their specialized functions. During development, CD11c+ microglia are crucial for the maturation of oligodendrocytes and the integrity of white matter, particularly in regions such as the corpus callosum and cerebellum. In preclinical models of neurodegenerative diseases (such as Alzheimer’s disease and amyotrophic lateral sclerosis) and central nervous system injuries (such as stroke and spinal cord injury), they are consistently associated with neuroprotective phenotypes. CD11c+ microglia exhibit enhanced phagocytic capacity near amyloid plaques and damaged neurons, helping to clear pathological protein aggregates and cell debris, thereby reducing neurotoxicity and promoting a repair environment. The current consensus is that specific microenvironmental cues, particularly hazard signaling molecules damage-associated molecular patterns and cytokines (such as interferon-γ), are the main drivers of the differentiation and activation of CD11c+ microglia. Among these, the TREM2-APOE signaling axis is a key and widely accepted regulatory pathway for their survival, proliferation, and functional status. The plasticity of CD11c+ microglia is regulated by multiple signaling pathways, including CSF1R, SIRPα-CD47, interferon-γ, and the complement cascade. Emerging therapeutic strategies aim to regulate their activities through gene targeting, metabolic intervention, and immune regulation using TREM2 agonists, CSF1R inhibitors, or nanopharmacological methods. However, challenges remain in defining specific CD11c+ biomarkers, understanding environment-dependent functions, and achieving targeted delivery. Future prospects depend on clearly addressing individual developmental issues, deciphering the molecular switches that control phenotypic plasticity, and developing highly specific therapeutic strategies to leverage their beneficial functions, thereby paving the way for new intervention methods for neurological diseases.  Related Articles | Metrics

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Artificial hibernation: A new technique for protecting neural tissue and organs Wuhua Pang, Ziqi Wang, Yuqi Lin, Yuhan Liu, Xiaoyu Wang, Mengguang Wei, Xiaoyin Li, Xuyi Chen 2026, 21 (10):  4550-4559.  doi: 10.4103/NRR.NRR-D-25-00025 Abstract ( 53 )   PDF (2633KB) ( 2 )   Save With the rapid development of life support technologies in the biomedical field, artificial hibernation has shown significant potential in the area of neural tissues and organ protection. This paper systematically reviews the three major technologies of artificial hibernation, as well as their operational procedures and the latest technological progress. It emphasizes the protective role of artificial hibernation technology on neural tissues and vital human organs, such as the brain, spinal cord, heart, kidneys, liver, and intestines, and explores its protective mechanisms. Based on an analysis of the existing literature, it was observed that artificial hibernation technology significantly lowers metabolic rate and decelerates pathological processes, consequently enhancing organ survival rates and functional recovery. This article explains the artificial hibernation technology, neural tissue and organs, and their relationships. By discussing the protective effects of the artificial hibernation technology on neural tissue and organs, it proves the therapeutic effects of this technology in diseases such as craniocerebral injury, extensive cerebral infarction, cerebral hemorrhage, neonatal hypoxic-ischemic encephalopathy and post-cardiopulmonary resuscitation encephalopathy. Furthermore, this paper addresses the clinical challenges associated with applying artificial hibernation for neuroprotection and organ preservation, while also outlining potential future development directions for the technology. Therefore, the exploration of how artificial hibernation technology protects neural tissue and organs provides a solid theoretical foundation for its future clinical application.  Related Articles | Metrics

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Beyond Neurons: The Impact of Cannabidiol on Glial Cells in Ischemic Stroke Victória Linden de Rezende, Khiany Mathias, Cinara Ludvig Gonçalves, Rafael Mariano de Bitencourt, Tatiana Barichello, Fabricia Petronilho 2026, 21 (10):  4560-4566.  doi: 10.4103/NRR.NRR-D-25-01029 Abstract ( 45 )   PDF (792KB) ( 2 )   Save Ischemic stroke triggers a complex cascade of events involving inflammation, oxidative stress, and glial cell dysfunction, all of which contribute to neuronal damage and impaired recovery. Glial cells (e.g., astrocytes, microglia, and oligodendrocytes) play key roles in neuroinflammatory responses, making them attractive targets for therapeutic modulation. Cannabidiol, a non-psychoactive phytocannabinoid from Cannabis sativa, exhibits anti-inflammatory, antioxidant, and neuroprotective properties. Preclinical evidence indicates that cannabidiol attenuates glial reactivity, reduces pro-inflammatory signaling, mitigates oxidative stress, and preserves blood–brain and intestinal barrier integrity in stroke models. Moreover, cannabidiol modulates key molecular pathways (e.g., nuclear factor-κB, tumor necrosis factor, and calcium-related signaling), contributing to reduced infarct volume and improved neurological function. Despite these promising effects, clinical translation is hindered by a lack of standardized formulations, dosing regimens, and human trials. This review highlights the impact of cannabidiol on glial cell activity in ischemic stroke, proposing it as a multi-target agent with therapeutic potential in post-stroke recovery and neuroprotection. Related Articles | Metrics

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Spatiotemporal disarray of inflammatory microenvironment following spinal cord injury Jiawei Di, Yubao Lu, Senyu Yao, Haojie Zhang, Zhenming Tian, Longyou Xiao, Zhizhong Shang, Lei He, Mao Pang, Yang Yang, Liangming Zhang, Liumin He, Bin Liu, Limin Rong 2026, 21 (10):  4567-4577.  Abstract ( 31 )   PDF (1968KB) ( 4 )   Save Spinal cord injury is a severe neurological condition with far-reaching consequences for both individuals and society. Its progression involves a complex interplay between the initial mechanical insult and inflammation-driven secondary injury. This review interprets recent studies on the spatiotemporal map of the inflammatory microenvironment in spinal cord injury and other neurological disorders, focusing on the latest mechanistic research and treatment options. The postinjury inflammatory microenvironment comprises diverse immune and glial cell populations whose phenotypes and functions change over time. The current consensus suggests that inflammation has a paradoxical nature: while it can limit lesion spread in the acute stage, chronic or dysregulated responses contribute to further neural damage through pathways such as excitotoxicity, oxidative stress, and glial scar formation. Methods such as spatiotemporal transcriptomic analyses and organoid-based models have improved our ability to resolve cell–cell interactions and discover new molecular targets. Numerous therapies targeting this microenvironment have been developed. Stem cell–based approaches, especially human umbilical cord mesenchymal stem cells, show promise in promoting tissue regeneration and immune regulation in experimental and early clinical studies. Bioengineering methods such as using biomaterial scaffolds and controlled drug release are being investigated to improve drug delivery and the injury microenvironment. Pharmacological efforts to modify cytokine networks, oxidative pathways, or immune checkpoints have achieved some success, hampered by patient heterogeneity and injury patterns. Persistent challenges include determining the context-specific mechanisms, identifying the best treatment windows, and combining a few methods for the best effect. In summary, detailed understanding of the spatiotemporal dynamics of post–spinal cord injury inflammation is essential for designing targeted interventions. Future directions include integrating multiomics datasets, identifying predictive biomarkers for patient stratification, and developing adaptive treatment protocols that fine-tune rather than suppress immune responses to promote neural repair and functional recovery. Related Articles | Metrics

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Mild and repetitive mild traumatic brain injury: Changes in microglial cells and synapses Adna Smajkan, Elizabeth Naranjo-Cinto, Florence M. Bareyre 2026, 21 (10):  4578-4593.  doi: 10.4103/NRR.NRR-D-25-00902 Abstract ( 38 )   PDF (3754KB) ( 0 )   Save Mild traumatic brain injury results from external mechanical forces to the head. Repetitive mild traumatic brain injury, characterized by multiple concussive events over time, is increasingly recognized in contact sports or domestic abuse. Repetitive injuries are associated with a greater risk of cumulative deficits and chronic neurodegenerative conditions. After a period of large focus on gross morphological changes following mild traumatic brain injury and repetitive mild traumatic brain injury, recent research is exploring more subtle yet critical changes at the synaptic and microglial levels. Novel findings indicate that even a single mild traumatic brain injury can induce transient alterations in synaptic function, including increased excitatory neurotransmission and disrupted synaptic plasticity. Parallel to synaptic changes, microglial cells, the brain’s resident immune cells, undergo rapid and prolonged activation after mild traumatic brain injury, including morphological transformation and functional activation. In repetitive mild traumatic brain injury, microglial priming is more pronounced, leading to sustained neuroimmune dysregulation and heightened and persistent vulnerability. In this review, we will summarize the current literature on mild traumatic brain injury and repetitive mild traumatic brain injury with a specific emphasis on microglial and synaptic changes. Related Articles | Metrics

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Error-prone translation as a driver of proteostasis collapse and neurodegeneration Rashid Akbergenov, David P. Wolfer, Dennis Gillingham, Dimitri Shcherbakov 2026, 21 (10):  4594-4602.  doi: 10.4103/NRR.NRR-D-25-00795 Abstract ( 64 )   PDF (7717KB) ( 0 )   Save Error-prone translation, resulting in inaccuracies in protein synthesis, is increasingly recognized as a critical contributor to proteostasis disruption and the pathogenesis of age-related neurological disorders. In recent years, numerous studies have elucidated that stochastic errors during mRNA translation may act as a molecular “tipping point” initiating pathogenic protein misfolding. A detailed analysis of how translation errors lead to protein misfolding, aggregation, and subsequent neurotoxicity will facilitate the identification of promising therapeutic targets for neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. This article explores the contribution of mistranslation to proteostasis decline, focusing on the unique vulnerabilities of neuronal cells. We review the sources of translation errors, effects of ribosomal ambiguity and error-restrictive mutations, role of proteostatic mechanisms (such as molecular chaperones, ubiquitin-proteasome system, and unfolded protein response), and provide a unified perspective that links age-related translational infidelity to neurodegeneration. By synthesizing the most recent data obtained with genetically modified cellular and animal model studies, we highlight how age-associated decline in translational fidelity exacerbates proteostasis failure and propose potential therapeutic interventions targeting translation accuracy to mitigate neurodegeneration. Related Articles | Metrics

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Stem cell models in ataxia-telangiectasia Maria Talmon, Giulia Lecchi, Luigia G. Fresu 2026, 21 (10):  4603-4607.  doi: 10.4103/NRR.NRR-D-25-00988 Abstract ( 45 )   PDF (1112KB) ( 0 )   Save Ataxia-telangiectasia is a rare neurodegenerative disease with a complex phenotype, which has recently been associated with alterations in metabolism, inadequate responses to oxidative stress and inflammation, as well as increased cardiovascular and tumor risk. All of these appear to be attributable to genetic mutations/variants in the ataxia-telangiectasia mutated gene, which encodes the ataxia-telangiectasia mutated protein. The possibility of a better phenotypic definition provides a basis for timely, personalized therapeutic intervention to reduce or prevent worsening of clinical symptoms. Several ataxia-telangiectasia mutated knock-out murine models were created, but none efficiently developed progressive ataxia, failing to recapitulate human neurodegeneration following ataxia-telangiectasia mutated deficiency. Furthermore, considering the strong awareness of the ban on the use of animals in scientific research, a great effort has been made and is still ongoing to create human cellular models of ataxia-telangiectasia with the aim of understanding in detail the molecular mechanisms of neurodegeneration and skeletal muscle defect, of being able to identify specific therapies. This review highlights human stem cell approaches as in vitro models that have been established as attempts to study the outcomes of ataxia-telangiectasia mutated inactivation regarding neurogenic and myogenic differentiation. The first attempts at differentiation from fetal tissues, through the induced pluripotent stem cell revolution and the latest urine-derived stem cells will be reviewed. Related Articles | Metrics

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Proteomic analyses in early brain development and neuropathological implications of fetal growth restriction Gemma C. Ventura, Kirat K. Chand, Paul B. Colditz, Julie A. Wixey 2026, 21 (10):  4608-4616.  doi: 10.4103/NRR.NRR-D-25-01234 Abstract ( 34 )   PDF (840KB) ( 1 )   Save Proteins are the primary functional units within cells, driving complex biological processes essential for stem cell differentiation into specific neural lineages and for the structural and functional maturation of the central nervous system. Advances in high-throughput proteomic technologies allow comprehensive profiling of molecular landscape of the brain, revealing dynamic, region- and time-specific changes in protein expression. During early embryonic development, pluripotency-associated proteins are highly expressed but gradually decline as lineagespecific markers and pathways governing DNA regulation and cytoskeletal organization become predominant. In fetal and postnatal stages, synaptic and metabolic proteins are enriched in a region-specific manner, reflecting functional compartmentalization and specialization in the central nervous system. Fetal growth restriction is an obstetric complication caused by sustained periods of inadequate oxygen and nutrient supply, preventing the fetus from achieving its genetic growth potential. Proteomic analysis of fetal tissues and biofluids has deepened our understanding of the molecular mechanisms associated with fetal growth restriction, highlighting metabolic and vascular adaptations, inflammatory responses and redox imbalances. These analyses have also uncovered molecular signatures with potential value as biomarkers for clinical diagnosis (e.g., complement proteins in maternal blood in fetal growth restriction), and prognosis (e.g., neurogenic locus notch homolog protein 1 as a modulator of fetal growth restriction response). Despite such advances, animal models remain indispensable for elucidating the multifactorial nature of fetal growth restriction-related neuropathology, pinpointing region-specific alterations. They also offer a controlled setting to explore how factors such as sex, gestational age at birth, and birth weight influence the impact of fetal growth restriction on brain development. A deeper understanding of neurodevelopmental processes and the pathological mechanisms involved in fetal growth restriction is critical for the development of effective diagnostic strategies and targeted therapeutic interventions. The purpose of this review is to provide synthesis of neuroproteomic alterations across developmental stages, highlighting how chronic intrauterine oxygen and nutrient deprivation, in humans and animals, shapes the proteomic landscape. Related Articles | Metrics

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Intranasal therapies for neonatal hypoxic-ischemic encephalopathy Andrew S. Cavanagh, Benjamin I. Sollinger, Nazli Kuter, Khyzer Aziz, Victoria Turnbill, Lee J. Martin, Frances J. Northington 2026, 21 (10):  4617-4622.  doi: 10.4103/NRR.NRR-D-25-01036 Abstract ( 33 )   PDF (4513KB) ( 0 )   Save Neonatal hypoxic-ischemic encephalopathy is the leading cause of brain injury in term infants worldwide and disproportionately affects low- and middle-income communities. Therapeutic hypothermia, the standard of care for hypoxic-ischemic encephalopathy in high-resourced settings, has no effect on morbidity and increases mortality after hypoxic-ischemic encephalopathy in low- and middle-income settings. Intranasal administration offers the opportunity to deliver more accessible treatments for all babies with neonatal hypoxic-ischemic encephalopathy due to lower resource needs, ease of administration, and the capacity to directly target the brain. We reviewed preclinical literature concerning intranasal treatments for hypoxic-ischemic encephalopathy and developed a novel semi-quantitative index ranking intranasal therapies for their potential for further development as biologically plausible, effective, and accessible treatments for hypoxic-ischemic encephalopathy. We searched PubMed and Google Scholar for peer-reviewed articles on intranasal therapies for hypoxic-ischemic encephalopathy using the mesh phrases “Neonatal hypoxic-ischemic encephalopathy intranasal” and “Neonatal brain intranasal.” Sixty-two studies were included that described thirty-four unique intranasal therapies. Neonatal intranasal therapies have been widely studied in small animal models, infrequently in large animals, and only recently in human clinical trials. Our semi-quantitative ranking revealed cell-based therapies as potentially the most effective and developed intranasal therapy in animal models of hypoxic-ischemic encephalopathy, though the pharmaceutical support compulsory to current cell-based treatments limits their accessibility in low-resourced settings. Intranasal therapies for neonatal hypoxic-ischemic encephalopathy have both feasibility and neuroprotective potential for safe, effective, and accessible treatment of hypoxic-ischemic encephalopathy. Additional research is needed for translation to humans. Future investigation should emphasize appropriate animal modeling with pharmaceutics and cells, combined with an evaluation of the brain connectome and neurobehavioral outcomes. Related Articles | Metrics

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Cell-based immunotherapy for neurodegenerative disease: current approaches and bright future Tomas J. Huerta, Valentina Urbina-Muñoz, Valentina Urra-Alvarez, Cristopher Villablanca, Luis S. Gomez-Perez, Barbara Saavedra, Tomás Contreras, René L. Vidal 2026, 21 (10):  4623-4632.  doi: 10.4103/NRR.NRR-D-25-00816 Abstract ( 35 )   PDF (4340KB) ( 2 )   Save Neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease are characterized by progressive neuronal loss and chronic neuroinflammation, with current treatments remaining largely symptomatic. This review explores the potential of cell-based immunotherapy as a disease-modifying strategy. Advances in stem cell biology and immune engineering have facilitated the development of therapies using mesenchymal stem cells, chimeric antigen receptor T cells, macrophages, regulatory T cells, modified macrophages, and monoclonal antibodies. These approaches aim to regulate immune mechanisms implicated in neurodegeneration, such as microglial activation, systemic inflammation, and immune checkpoint dysregulation. Notably, macrophage-mediated delivery systems, such as genetically modified cells expressing neurotrophic factors or antioxidant enzymes, have demonstrated neuroprotective effects. Likewise, emerging data support T-cell modulation and monoclonal antibody development as therapeutic targets in amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. We highlight current preclinical findings, underlying mechanisms, and translational challenges, emphasizing that immunomodulatory cell therapies represent a promising avenue for precision medicine in neurodegenerative diseases. Related Articles | Metrics

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Metabolic reprogramming of microglia: effects on development, disease, and therapeutic potential Haiwei Zhang, Mengmeng Jin, Peng Jiang, Ying Liu 2026, 21 (10):  4633-4641.  doi: 10.4103/NRR.NRR-D-25-01298 Abstract ( 38 )   PDF (3499KB) ( 0 )   Save Microglia, the immune sentinels of the central nervous system, play vital roles in maintaining neural homeostasis and mediating responses to injury and disease. Their functions, including synaptic pruning to neuroinflammation, are tightly linked to their metabolic state. Emerging evidence suggests that metabolic reprogramming is a key driver of microglial activation, functional transitions, and interactions with neurons and other glial cells. This review summarizes current findings on the developmental origins, region-specific adaptations, and metabolic plasticity of microglia. We review lipid metabolism, energy utilization, and oxidative stress responses, which underlie immune regulation and neuroprotective functions. By integrating molecular, transcriptomic, and metabolomic insights, we provide a comprehensive understanding of microglial metabolism and highlight potential therapeutic strategies targeting metabolic pathways in neurodegenerative and central nervous system diseases. Related Articles | Metrics

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Mechanisms and biomarkers of poststroke cognitive impairment Mengxia Liu, Manqing Zhang, Zhiying Chen, Bing Bao, Yanghang Chen, Fangfang Wang, Min Jiang, Moxin Wu, Xiaoping Yin 2026, 21 (10):  4642-4652.  doi: 10.4103/NRR.NRR-D-25-00674 Abstract ( 47 )   PDF (5057KB) ( 3 )   Save Poststroke cognitive impairment is a common neurological complication in stroke patients, characterized by progressive cognitive decline ranging from mild cognitive impairment to vascular dementia, significantly impacting patients’ quality of life and long-term prognosis. Recent studies have gradually unveiled the multidimensional pathophysiological mechanisms underlying post-stroke cognitive impairment. This review provides a detailed introduction to the mechanisms and biomarkers of poststroke cognitive impairment. At the molecular level, the development of poststroke cognitive impairment involves multi-level and interconnected pathophysiological changes. Among these, the activation of neuroinflammation and oxidative stress damage are considered key initiating factors. Concurrently, the accumulation of reactive oxygen species induced by oxidative stress can further promote the occurrence of poststroke cognitive impairment. Increased blood–brain barrier permeability, along with the infiltration of peripheral inflammatory cells and the entry of toxic substances into the brain, exacerbates neural damage. In terms of neurotransmitter systems, the imbalance between excitatory and inhibitory neurotransmitter systems directly affects synaptic plasticity and the integration of neural networks. Structurally, the integrity of white matter microstructure is compromised, manifesting as myelin loss and axonal transport impairment. These multi-level pathological changes interact through complex positive feedback mechanisms, collectively forming the pathogenic network of poststroke cognitive impairment. In the field of biomarker research, a six-dimensional classification system for post-stroke cognitive impairment biomarkers has been reported, systematically categorizing relevant biomarkers into metabolic markers, inflammatory factor profiles, genetic markers, blood–brain barrier damage indicators, gut microbiota characteristics, and neuroimaging biomarkers. Notably, the integrated predictive model developed by combining serum biomarkers with multimodal neuroimaging features significantly enhances the diagnostic specificity of poststroke cognitive impairment biomarkers. This multidimensional and systematic research approach provides new perspectives for the in-depth analysis of the pathogenesis of poststroke cognitive impairment biomarkers and offers important targets for early clinical intervention. In the future, it is hoped that dynamic monitoring of the temporal changes in these biomarkers can more accurately assess the effectiveness of interventions and guide the optimization and adjustment of treatment plans. Based on risk assessment results, a tiered management approach should be implemented: high-risk patients should undergo cognitive assessments and biomarker testing every three months, while moderate-to-low-risk patients should follow a stepwise monitoring protocol. This precision management model can predict the risk of cognitive decline up to 6–12 months in advance, enabling timely interventions to reduce the incidence of severe cognitive impairment. Mechanistic studies and biomarker discovery for poststroke cognitive impairment have brought breakthrough progress to clinical diagnosis and treatment. Future research should continue to explore its molecular mechanisms, develop more effective targeted therapeutic drugs, establish a comprehensive early warning and personalized treatment system, and ultimately achieve precise prevention, control, and optimized management of poststroke cognitive impairment.  Related Articles | Metrics

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Extracellular vesicles: A new therapeutic drug for nerve injury repair. Jinyi Cai, Chongkang Ren, Changshui Wang, Songmin Shen, Biao Xu, Changmeng Cui 2026, 21 (10):  4653-4663.  doi: 10.4103/NRR.NRR-D-25-00133 Abstract ( 53 )   PDF (6880KB) ( 3 )   Save Extracellular vesicles are membranous structures actively released by cells. They efficiently mediate intercellular communication and play a role in reshaping the microenvironment. Their diverse bioactive cargo, including miRNAs, proteins, and lipids, along with their ability to cross the blood–brain barrier, holds broad therapeutic promise in the field of neuroregeneration. Current research focuses on exploring the mechanisms of action and clinical translational potential of extracellular vesicles from different sources, including exosomes derived from mesenchymal stem cells, neural stem cells, neurons, and vascular cells, in neural repair. Key issues restricting clinical translation include the lack of standardized isolation and characterization methods, insufficient dose determination and bioavailability assessment, and inadequate evidence for long-term safety. This review systematically summarizes the therapeutic research progress of extracellular vesicles from various sources in neurological disorders such as brain injury, spinal cord injury, and neurodegenerative diseases. It provides a comprehensive overview of the key molecular regulatory networks involving extracellular vesicles, including the regulation of neuroinflammation, axonal regeneration, mitochondrial function and metabolic homeostasis, as well as structural and functional support of the neurovascular unit. In addition, this review assesses the feasibility of extracellular vesicles as drug delivery vehicles. In summary, extracellular vesicles constitute a dynamic and multi-pathway regulatory network. A thorough elucidation of their mechanisms of action is expected to facilitate the development of novel therapeutic strategies in the field of neural repair and provide new perspectives and solutions for precision medicine.  Related Articles | Metrics

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Therapeutic potential of ultrasound for spinal cord injury Ederlyn M. Perolina, Brad J. Raos, Maria Asplund, Darren M. Svirskis, Sachin S. Thakur 2026, 21 (10):  4664-4673.  doi: 10.4103/NRR.NRR-D-25-00978 Abstract ( 35 )   PDF (1606KB) ( 2 )   Save Spinal cord injury is a debilitating condition that often results in permanent impairments in motor, sensory, and autonomic functions. The potential for treating spinal cord injury with ultrasound is increasingly being recognized. Ultrasound addresses several key aspects of spinal cord injury, including promoting nerve healing by creating a regenerative environment, attenuating inflammation, and managing secondary complications. While preclinical studies show encouraging results, further translational efforts are necessary to adapt these therapies for clinical use. Insights gained from transcranial ultrasound applications, such as transducer selection, anatomical considerations, and pre-treatment planning, can provide valuable guidance for optimizing ultrasound treatments for spinal cord injury. This literature review highlights the exciting potential of ultrasound therapy in spinal cord injury research and the importance of refining treatment parameters and strategies for successful clinical translation. Related Articles | Metrics

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Intercellular communication between peripheral monocytes and central nervous system cells in stroke Masato Kanazawa, Masahiro Hatakeyama 2026, 21 (10):  4674-4679.  doi: 10.4103/NRR.NRR-D-25-00738 Abstract ( 43 )   PDF (1928KB) ( 1 )   Save Stroke, particularly ischemic stroke, induces dynamic interactions between peripheral monocytes and central nervous system cells, influencing neuroinflammation, repair, and functional recovery. Monocytes infiltrate the brain post-stroke and differentiate into macrophages, which interact with microglia, astrocytes, endothelial cells, and neurons. These interactions, mediated by chemokines, cytokines, and extracellular vesicles, can be detrimental or beneficial depending on context. Another interface is the gut–immune–brain axis, wherein gut microbiota, immune cells, and central nervous system-resident populations engage in reciprocal communication. Emerging therapies targeting monocyte subsets, their recruitment, and communication pathways. These include preconditioned peripheral blood mononuclear cells, bone marrow-derived mononuclear cells, mesenchymal stem cells, and cellfree or cell-mediated approaches utilizing the secretome. Together, these interventions hold promise for enhancing stroke recovery by modulating the immune–neural interface. This review summarizes recent advances in monocyte–central nervous system communication and its translational potential in stroke. Related Articles | Metrics

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Advancements in differentiation of induced pluripotent stem cells into specialized neuronal subtypes Selena Setsu, Hideyuki Okano, Satoru Morimoto 2026, 21 (10):  4680-4689.  doi: 10.4103/NRR.NRR-D-25-00630 Abstract ( 31 )   PDF (1320KB) ( 2 )   Save The ability to generate specialized human neurons from induced pluripotent stem cells has revolutionized neuroscience, regenerative medicine, and drug discovery. Since their discovery, induced pluripotent stem cells have emerged as an ethically favorable and versatile platform to model human neurological diseases, offering new insights beyond traditional animal models. In the past decade, rapid advances have enabled the efficient differentiation of induced pluripotent stem cells into diverse neuronal subtypes, including glutamatergic neurons, GABAergic neurons, dopaminergic neurons, serotonergic neurons, motor neurons, sensory neurons, Purkinje cells, sympathetic neurons, parasympathetic neurons, and noradrenergic neurons. Tailored combinations of developmental signaling molecules, transcription factor programming, and small molecule modulation have dramatically improved the reproducibility, scalability, and functional maturity of these differentiated neurons. These advancements are particularly timely as they underpin the next generation of disease modelling platforms, high-throughput drug screening systems, and emerging cell-based therapies for conditions such as Parkinson’s disease, amyotrophic lateral sclerosis, epilepsy, and Alzheimer’s disease. Moreover, the field is moving toward standardized, chemically defined protocols and improved validation pipelines, including electrophysiological assays and molecular profiling, to ensure the authenticity and maturity of induced pluripotent stem cell-derived neurons. Notably, recent breakthroughs in sympathetic and parasympathetic neuron derivation are expanding the scope of induced pluripotent stem cell technology into autonomic nervous system research and cardiac neuromodulation studies. However, challenges remain, including variability across induced pluripotent stem cell lines, incomplete neuronal maturation, and scalability constraints for clinical-grade applications. Addressing these hurdles through optimization of patterning cues, co-culture systems, and advanced bioprocessing strategies will be crucial to realizing the full translational potential of induced pluripotent stem cell-derived neurons. Collectively, the methodologies and developments summarized here mark a major step toward achieving faithful, efficient, and scalable generation of human neurons in vitro, laying the foundation for personalized neurology and regenerative medicine. Related Articles | Metrics

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Retinal proteomics in neurodegeneration: Insights into ocular and brain disorders Shahab Mirshahvaladi, Bhakta Prasad Gaire, Sara Assar Kashani, Aparajeeta Guha, Yosef Koronyo, Dieu-Trang Fuchs, Yuyi You, Keith L. Black, Joao A. Paulo, Stuart L. Graham, Vivek Gupta, Mehdi Mirzaei, Maya Koronyo-Hamaoui 2026, 21 (10):  4690-4703.  doi: 10.4103/NRR.NRR-D-25-00291 Abstract ( 31 )   PDF (7330KB) ( 0 )   Save Dysregulated proteome in the retina represents a promising avenue for discovering novel therapeutic targets and noninvasive diagnostic biomarkers for neurodegenerative diseases with ocular manifestations. Advanced mass spectrometry–based proteomics techniques have shown considerable potential in investigating the retinal proteome in diseases such as glaucoma, age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, as well as Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease. Recent proteomics innovations are overcoming challenges such as limited sample size and protein coverage that previously hindered comprehensive retinal proteome analysis. Notably, the incorporation of artificial intelligence–driven computational pipelines, including Graphics Processing Unit-accelerated deep learning architectures, has markedly enhanced the precision and effectiveness of retinal proteomics. These advances facilitate high-resolution identification of novel protein signatures within large-scale multi-omics datasets. Furthermore, the integration of advanced artificial intelligence with state-of-the-art big data infrastructures supports the early detection of biomarkers and therapeutic targets in neurodegenerative diseases with ocular involvement, offering unprecedented disease specificity and sensitivity. In addition to these computational strides, emerging complementary and alternative technologies continue to provide valuable tools for retinal analysis, expanding the potential for identifying biomarker and therapeutic targets in both ophthalmic and neurodegenerative disorders. This review summarizes recent advancements in retinal proteomics, with a particular focus on neurodegenerative and ocular diseases. Related Articles | Metrics

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Targeting innovative therapeutic approaches to the hallmarks of aging to combat Alzheimer's disease Michal Izrael, Orli Miriam Frenkel 2026, 21 (10):  4704-4714.  doi: 10.4103/NRR.NRR-D-25-00966 Abstract ( 45 )   PDF (1749KB) ( 1 )   Save Aging is the leading risk factor for neurodegenerative diseases, including Alzheimer’s disease. Mounting evidence implicates twelve interconnected hallmarks of aging, such as genomic instability, mitochondrial dysfunction, cellular senescence, and altered intercellular communication, as core contributors to cognitive decline. In this review, we will first delineate the hallmarks of aging and their mechanistic roles according to their functions in the aging brain and Alzheimer’s disease. These hallmarks can be grouped into four major functional clusters: (i) Genomic and epigenomic instability, (ii) proteostasis and organelle dysfunction, (iii) cellular fate and regenerative decline, and (iv) cellular senescence. Then, we provide an overview of innovative therapeutic approaches aimed at modifying these hallmarks, focusing on the emerging paradigm of supplementation of rejuvenation factors that are derived from young plasma, stem cell secretomes, or their derivatives (e.g., extracellular vesicles). Finally, we discuss key aging-related biological factors that can influence Alzheimer’s disease progression and evaluate their potential as therapeutic targets.  Related Articles | Metrics

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O-GlcNAcylation: A molecular switch linking brain health to neurodegeneration Nan Shao, Xiaoyan Zhang, Yunzhi Ge, Jiaxuan Tang, Huawu Gao, Wenwen Si, Biao Cai 2026, 21 (10):  4715-4728.  doi: 10.4103/NRR.NRR-D-25-00101 Abstract ( 48 )   PDF (12028KB) ( 1 )   Save Neurodegenerative disorders are typically caused by harmful protein accumulation and nerve cell damage. A post-translational modification called O-linked N-acetylglucosamine ylation acts as a critical regulator in these disorders by controlling protein behavior, cell signaling, and energy balance. This modification is dynamically balanced through the cooperative actions of O-linked N-acetylglucosamine transferase and O-GlcNAcase. In healthy brains, O-GlcNAcylation supports nerve cell function and survival, but its imbalance contributes to disease progression. Notably, the effects of O-GlcNAcylation differ across disorders. This review reveals how O-GlcNAcylation bridges molecular mechanisms to neurodegeneration, as well as the prospects of targeted O-linked N-acetylglucosamine acylation therapy for neurodegenerative diseases. In Alzheimer’s disease, it blocks toxic changes in key proteins like tau and amyloid-beta. In Parkinson’s disease, it reduces the clumping of alpha-synuclein, yet may disrupt dopamine production. In amyotrophic lateral sclerosis, it protects nerve fiber transport systems. Additionally, O-GlcNAcylation plays an indispensable part in other neurodegenerative conditions, including Huntington’s disease, aging, Machado- Joseph disease, multiple sclerosis, and giant axonal neuropathy. New therapies targeting this mechanism include glucosamine supplements and O-GlcNAcase inhibitors, which show clinical promise but face translational challenges.  Related Articles | Metrics

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Nuclear membrane disruption in neurodegenerative diseases: Emerging perspectives Shuo Yuan, Nicholas Essepian, Qingbo Wang, Lulu Jiang 2026, 21 (10):  4729-4733.  doi: 10.4103/NRR.NRR-D-25-01127 Abstract ( 34 )   PDF (2884KB) ( 0 )   Save The nucleus, as the largest organelle within the cell, serves as the central hub for storing, replicating, and transcribing genetic information, thereby orchestrating vital cellular processes. In eukaryotic cells, the nuclear membrane is composed of several structural components: the outer and inner nuclear membranes, the nuclear pore complexes, and the underlying nuclear lamina, which together preserve the stability of the intracellular environment. Neurodegenerative disorders, such as Alzheimer’s disease and related dementias, are characterized by the gradual degeneration and loss of neuronal structure and function in the central nervous system. Growing evidence suggests that alterations in nuclear envelope architecture are closely associated with the onset and progression of these diseases. This article summarizes the information, focusing on the regulators of the cell nuclear membrane, as well as its pathophysiological processes and regulatory mechanisms in neurodegenerative diseases. Moreover, this paper discusses related research advances that provide novel insights into a deeper understanding of the nuclear membrane in disease progression and its potential as a therapeutic target. Related Articles | Metrics

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Organoids: Key advances, optimization, and technological iterations in their application to neurodegenerative diseases. Jiangyu Zhao, Jing Wang, Xing Guo 2026, 21 (10):  4734-4744.  doi: 10.4103/NRR.NRR-D-25-00924 Abstract ( 43 )   PDF (6350KB) ( 0 )   Save Organoid technology, as an innovative approach, has shown great potential in disease modeling, target screening, and the development of treatment strategies. However, traditional organoids still have three major limitations in research: the absence of specific cell types, the lack of blood–brain barrier structure, and insufficient reproducibility of experimental results. In recent years, researchers have gradually overcome these limitations by introducing innovative techniques such as advanced culture methods, microfluidic systems, bioprinting, organoid transplantation, and assembloid construction. This progress has facilitated the widespread application of organoids in the study of neurodegenerative diseases. This paper aims to systematically review the technological innovations of organoids in the study of neurodegenerative diseases. By summarizing classical organoid construction strategies and their limitations, it emphasizes the value of organoids in comprehensive applications within neurodegenerative disease research. In this review, we focus on five specific neurodegenerative diseases: Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Research in these diseases demonstrates that organoids improve experimental accessibility and reduce development cycles in disease modeling, target discovery, and therapeutic strategy formation. Using customized equipment and gene editing techniques, these organoids can be tailored to specific needs, providing pathophysiologically relevant disease models and enhancing our understanding of neurodegenerative diseases. Although organoid technology has demonstrated significant advantages in disease research, its potential for treating neurodegenerative diseases has not yet been fully explored, which may become an important direction for future research. Related Articles | Metrics

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Mitochondria-associated endoplasmic reticulum membranes and calcium ion exchange: A novel direction for aging and neurodegenerative diseases Yuxuan Yang, Mengjie Chen, Lingling Ding, Jiaxi Liu, Jiansheng Luo, Ruyu Yan, Jiaqi Ning, Siyi Xie, Xiang Li, Zhihao Ren, Ruiling Zhou, Zhuoya Chen 2026, 21 (10):  4745-4757.  doi: 10.4103/NRR.NRR-D-25-00857 Abstract ( 37 )   PDF (6599KB) ( 0 )   Save Mitochondria-associated endoplasmic reticulum membranes serve as crucial signaling hubs mediating communication between the endoplasmic reticulum and mitochondria, and play a central role in calcium ion exchange. This dynamic interface regulates key cellular processes including bioenergetic metabolism, apoptosis, autophagy, and stress responses. Dysregulation of calcium transport associated with mitochondria-associated endoplasmic reticulum membranes can disrupt intracellular homeostasis, leading to mitochondrial dysfunction, oxidative stress, and neuronal death, which are hallmarks of aging and neurodegenerative diseases. This review systematically examines the functions of protein complexes within mitochondria-associated endoplasmic reticulum membranes and the pathogenic mechanisms of calcium signaling regulated by these membranes in neurodegenerative disorders. It places particular emphasis on structural alterations in calcium ion transport machinery as a common mechanism underlying various neurodegenerative diseases. In Alzheimer’s disease, mitochondria-associated endoplasmic reticulum membranes exhibit a hyperactive state, promoting the generation of amyloid-β and enhancing calcium ion flux from the endoplasmic reticulum to the mitochondria. In contrast, in Parkinson’s disease and amyotrophic lateral sclerosis, the activity of mitochondria-associated endoplasmic reticulum membranes is reduced, leading to a decline in mitochondrial calcium ion buffering capacity and exacerbating excitotoxicity. Proteins residing in mitochondria-associated endoplasmic reticulum membranes are disrupted across various neurodegenerative diseases, resulting in abnormal communication between the endoplasmic reticulum and mitochondria. Recent studies indicate that mitochondria-associated endoplasmic reticulum membranes play a bidirectional role in disease progression, and compensatory mechanisms often exacerbate the pathological process. Therapeutic strategies aimed at preserving the integrity of mitochondria-associated endoplasmic reticulum membranes hold promise for alleviating neurodegenerative damage. Therefore, calcium ion exchange mediated by mitochondria-associated endoplasmic reticulum membranes plays a key role in aging and neurodegenerative diseases, making it a highly promising therapeutic target. Related Articles | Metrics

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High mobility group box 1 and its post-translational modifications: Molecular mechanisms underlying neurodegenerative disease pathogenesis Jun Li, Naming Wu, Yifan Xiao, Yiyuan Xia 2026, 21 (10):  4758-4768.  doi: 10.4103/NRR.NRR-D-25-01091 Abstract ( 47 )   PDF (3127KB) ( 2 )   Save High mobility group box 1 is a dynamic nuclear protein that acts as a damage-associated molecular pattern when released from cells and plays key roles in neurodegenerative diseases. This review comprehensively analyzes the related post-translational modifications that affect the dual functions of high mobility group box 1 in neuroinflammation and neuronal survival, including acetylation, phosphorylation, oxidation, S-nitrosylation, lactylation, and ubiquitination. Post-translational modifications play critical regulatory roles in high mobility group box 1 subcellular localization, release processes and the specificity of receptor binding. In Alzheimer’s disease, high mobility group box 1 exacerbates the disease through the Toll-like receptor 4/nuclear factor kappa B signaling pathway. Inhibition of high mobility group box 1 acetylation can alleviate neuroinflammation. Parkinson’s disease models indicate that the S-nitrosylation of Cys106 is essential for the secretion of high mobility group box 1, which contributes to dopaminergic degeneration through the activation of microglia. In multiple sclerosis, high mobility group box 1 obstructs remyelination by inhibiting the maturation of oligodendrocytes and activating pro-inflammatory pathways. In contrast, high mobility group box 1 can maintain autophagy and DNA repair functions, suggesting its protective role. Therapeutic strategies targeting high mobility group box 1 show potential benefits. Glycyrrhizic acid inhibits disulfide-linked high mobility group box 1, SIRT activators suppress acetylation, and anti-high mobility group box 1 antibodies neutralize extracellular isoforms, thereby improving the results of preclinical studies. However, the diverse functions of high mobility group box 1 and the lack of post-translational modification-specific biomarkers present challenges for clinical translation. Future research should aim to create selective inhibitors that can cross the blood-brain barrier to target harmful forms of high mobility group box 1, and establish post-translational modification-based biomarkers for early detection. This review emphasizes that accurately targeting of high mobility group box 1 post-translational modifications in neurodegenerative diseases could be a new approach that can interrupt neuroinflammatory cascades while maintaining neuroprotective functions. Related Articles | Metrics

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Neuroinflammation and noradrenergic modulation with β2-adrenoceptors: Emerging therapeutic targets for Parkinson’s diseases Maria Micaelle Gomes Tavares, Milena Caroline Nunes Monteiro de Carvalho, Mylaine Santos Mendonça, Iasmin de Carvalho Dantas, Katty Anne Amador de Lucena Medeiros, José Ronaldo dos Santos, Auderlan Mendonça de Gois 2026, 21 (10):  4769-4776.  doi: 10.4103/NRR.NRR-D-25-00903 Abstract ( 35 )   PDF (1238KB) ( 0 )   Save Neurodegenerative disorders, such as Parkinson’s disease, are strongly influenced by neuroinflammatory processes and dysfunction of the locus coeruleus-noradrenergic system. The locus coeruleus-noradrenergic system plays a pivotal role in modulating neuroinflammation and maintaining homeostatic regulation in the central nervous system. This review discusses the structural and functional aspects of the locus coeruleus-noradrenergic system and its interaction with immune responses. We examine how neuroinflammation contributes to disease progression, with a focus on glial activation and peripheral-central immune communication. Additionally, we analyze the impact of β-adrenoceptor-targeting drugs, highlighting the contrasting roles of β-blockers and β2-adrenoceptor agonists in neurodegeneration. While β-blocker, particularly non-selective agents like propranolol, have been associated with exacerbated neuroinflammation and Parkinson’s disease risk, β2-adrenoceptor agonists demonstrate neuroprotective effects by modulating microglial phenotypes, reducing α-synuclein aggregation, and enhancing neurotrophic support. Finally, we explore the canonical and non-canonical β2-adrenoceptor signaling pathways implicated in neuroprotection. Collectively, this review supports β2-adrenoceptors as promising therapeutic targets and underscores the need for further studies to elucidate their mechanistic roles in modulating neurodegenerative processes. Related Articles | Metrics

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Sex hormones, the gut microbiome, and neurodegenerative diseases: Lifespan perspective Sarah Stahlke, Carsten Theiss 2026, 21 (10):  4777-4784.  doi: 10.4103/NRR.NRR-D-25-00932 Abstract ( 40 )   PDF (2183KB) ( 0 )   Save The gut–brain axis represents a highly integrated communication network, connecting the gastrointestinal tract and the central nervous system via neural, immune, endocrine, and metabolic pathways. Steroid hormones, such as estrogens, androgens, and glucocorticoids, play a pivotal role in modulating these interactions across the lifespan. These hormones influence the composition of microbiota, intestinal permeability, and neuroimmune responses, thereby shaping brain function and behavior. Emerging evidence suggests a correlation between disruptions in the gut–brain axis and the onset and progression of neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, and multiple sclerosis. The diseases exhibit distinct sex-specific patterns in terms of prevalence, symptomatology, and progression. These patterns are often the consequence of differences in steroid hormone levels, receptor distribution, and immune responses. Despite these differences, the role of sex as a biological variable remains underrepresented in experimental and clinical research. This review synthesizes current evidence on how steroid hormones modulate gut–brain axis interactions and how these mechanisms contribute to neurodegeneration in a sex-specific manner. We highlight recent findings on hormonal regulation of the gut microbiome and its impact on neuroinflammation and neuronal vulnerability. This overview focuses not only on Parkinson’s disease, in which genetic variations in the gene for brain-derived neurotrophic factor have been observed among others as triggers for dopaminergic neurodegeneration. In addition, Alzheimer’s disease and multiple sclerosis are also considered, in which the prevalence of intestinal dysbiosis and impaired intestinal barrier function have been identified as significant influencing factors. This review provides a comprehensive framework for understanding the gender-specific neurobiology of gut–brain axis by integrating perspectives from the fields of endocrinology, neuroimmunology, and microbiome research. It is argued that a targeted investigation of the interactions between hormones and gut–brain axis is essential for the development of sex-specific therapeutic strategies for neurodegenerative diseases. Related Articles | Metrics

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Autophagy and selective autophagy receptors: Key players against Alzheimer’s disease Krenare Bruqi, Flavie Strappazzon 2026, 21 (10):  4785-4797.  doi: 10.4103/NRR.NRR-D-25-00976 Abstract ( 30 )   PDF (4767KB) ( 1 )   Save The devastating neurodegenerative disorder of Alzheimer’s disease hallmarks the presence of protein aggregates known as amyloid-β plaques and neurofibrillary tangles, composed of amyloid-β peptides and aberrantly phosphorylated Tau protein, respectively. The accumulation of these inclusions leads to significant alterations in neuronal homeostasis and overall brain function, resulting in a progressive and rapid cognitive decline. Autophagy, the molecular mechanism of cellular waste removal through the lysosomal pathway, accounts for the degradation of both amyloid-β plaques and neurofibrillary tangles in the brain, conferring therefore protection against the pathology. In addition to general autophagy, several lines of evidence have reported the implication of selective autophagy receptors, including sequestosome 1/p62, the neighbor of BRCA1 gene, the nuclear-dot protein 52, and optineurin, in mediating the autophagic clearance of amyloid-β, phosphorylated Tau, or both. Herein, we have highlighted autophagy and selective autophagy as pivotal mechanisms in Alzheimer’s disease, underlining selective autophagy receptors as a potential target for treatments in the future. Related Articles | Metrics

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Prospect in Alzheimer’s disease integrative therapy targeting both amyloid-β and Tau Wei Zhang, Yiqun Zhou, Jiuyan Chen, Miranda Perez, Xiomara Claure, Roger M. Leblanc 2026, 21 (10):  4798-4802.  doi: 10.4103/NRR.NRR-D-24-00916 Abstract ( 33 )   PDF (2812KB) ( 1 )   Save Alzheimer’s disease is well characterized by the buildup of amyloid-β plaques and tau protein tangles, leading to neurodegeneration and cognitive impairments. Recent prosperous Alzheimer’s disease therapeutic development targeting amyloid-β validates the amyloid hypothesis. Nonetheless, the limited efficacy of single-target therapies plus as-observed synergy between amyloid-β and tau calls for a thorough understanding of Alzheimer’s disease pathogenesis. Thus, this review introduces Alzheimer’s disease pathogenesis, specifically focusing on the amyloid-β and tau pathologies, highlights their interconnected nature, presents personal perspectives on therapeutic and diagnostic challenges, and underscores the necessity of combined therapeutic approaches to effectively address Alzheimer’s disease. Related Articles | Metrics

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Interplay of GBA1 with lysosomal dysfunction and inflammation in Parkinson's disease Ruochen Wang, Taku Hatano, Nobutaka Hattori, Davide Cossu 2026, 21 (10):  4803-4812.  doi: 10.4103/NRR.NRR-D-25-01082 Abstract ( 37 )   PDF (5396KB) ( 0 )   Save Mutations in the glucocerebrosidase (GBA1) gene, encoding the lysosomal enzyme glucocerebrosidase, represent the most significant genetic risk factor for Parkinson’s disease. These variants define a distinct clinical subtype characterized by earlier onset, accelerated motor decline, and pronounced cognitive impairment. This review synthesizes current insights into the molecular mechanisms linking GBA1 dysfunction to lysosomal failure, α-synuclein aggregation, and neuroinflammation. Pathogenic alleles such as N370S and L444P disrupt sphingolipid metabolism, resulting in toxic accumulations of glucosylceramide and glucosylsphingosine, endoplasmic reticulum stress, and impaired clearance of misfolded proteins. This initiates a self-reinforcing cycle in which glucocerebrosidase deficiency promotes α-synuclein aggregation, which subsequently impairs glucocerebrosidase trafficking. We explore the convergence of GBA1 mutations on the lysosomal–mitochondrial–autophagy axis, where impaired autophagic flux and disrupted organelle crosstalk amplify oxidative stress and activate the NLR family pyrin domain containing 3 inflammasome. The contribution of microglia, astrocytes, and oligodendrocytes to the neuroinflammatory cascade is eamined, along with the emerging influence of the microbiome-gut-brain axis in disease progression. Finally, we evaluate emerging therapeutic strategies, including pharmacological chaperones, NLRP3 inhibitors, adenoassociated virus-based gene therapy, and microbiome modulation, highlighting both promises and translational challenges such as blood–brain barrier penetration and mutation-specific efficacy. We conclude by advocating for precision medicine approaches, supported by robust biomarker development and advanced disease models, to guide tailored interventions for this aggressive Parkinson’s disease subtype. Related Articles | Metrics

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Treatment of animal models of Alzheimer’s disease with extracellular vesicles or exosomes and involvement of microRNAs Bridget Martinez, Philip V. Peplow 2026, 21 (10):  4813-4821.  doi: 10.4103/NRR.NRR-D-25-01116 Abstract ( 48 )   PDF (625KB) ( 1 )   Save Alzheimer’s disease is a complex and devastating neurodegenerative disorder that accounts for roughly 80% of all dementia cases. It is primarily marked by the accumulation of senile amyloid-β plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein. These pathological features are accompanied by chronic neuroinflammation and glial cell dysfunction, which collectively contribute to the progressive loss of synapses and neurons. As a result, individuals with Alzheimer’s disease experience gradual memory loss and cognitive decline. Currently, the global patient population is nearing 50 million, a number expected to increase dramatically over the coming decades. Conventional treatments focus on symptom management through acetylcholinesterase inhibitors, such as donepezil, galantamine, and rivastigmine, and the N-methyl-D-aspartate receptor antagonist memantine. However, the past few years have seen the approval of newer agents such as sodium oligomannate, aducanumab, and lecanemab, which show some promise in slowing disease progression. Unfortunately, most patients are not diagnosed until moderate or advanced stages when irreversible brain damage has occurred. This highlights an urgent need for early diagnosis and biomarkers together with therapeutic strategies aimed at early-stage intervention and identifying novel drug targets that address prodromal and established forms of the disease. This article is a literature review of extracellular vesicles/exosomes treatment in animal models of Alzheimer’s disease involving microRNAs. In the in vivo animal studies of Alzheimer’s disease reviewed, extracellular vesicles and exosomes from various sources improved memory and cognitive decline, lowered inflammation and amyloid deposition, and increased neuron survival in the brain. Loading extracellular vesicles and exosomes with microRNA mimics (e.g., miR-22, -29b, -124, -132, -138-5p, -342-5p, -711, and -7670-3p) or antagomirs (e.g., miR-206-antagomir) improved outcomes in animal models of Alzheimer’s disease. Supporting results were found in the in vitro cell studies reviewed. Related Articles | Metrics

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Retinal glial cells in glaucoma and age-related retinal diseases: Inflammatory responses, disease transitions, and translational perspectives. Akanksha Salkar, Viswanthram Palanivel, Devaraj Basavarajappa, Benjamin Heng, Angela Schulz, Vivek Gupta, Stuart Graham, Mehdi Mirzaei, Yuyi You 2026, 21 (10):  4822-4831.  doi: 10.4103/NRR.NRR-D-25-01905 Abstract ( 31 )   PDF (5587KB) ( 0 )   Save Microglia, Müller cells, and astrocytes play a crucial role in maintaining retinal structure, homeostasis, and neuronal function. In disease, they undergo reprogramming that drives chronic inflammation and neurodegeneration. Unique to the retina, these glial cells occupy specialized niches and interact closely with the blood–retinal barrier, creating distinct vulnerabilities. We summarized the glial activation mechanisms, shared triggers, including oxidative stress, metabolic dysfunction, aging, and systemic inflammation, as well as key pathways, such as nuclear factor kappa-B, mitogen-activated protein kinase, Janus kinase/signal transducer and activator of transcription, the inflammasome, and the complement system. Disease-specific responses in glaucoma, age-related macular degeneration, diabetic retinopathy, and vascular occlusions were compared, highlighting the heterogeneity of gliosis and its impact on neuronal and vascular pathology. We also discussed emerging human-derived platforms alongside proteomics approaches, highlighting their utility for mechanistic insights and discovering biomarkers. Despite advances, critical gaps remain in understanding glial–glial interactions and in developing robust models focused on glia. Despite these advances, major gaps remain in our understanding of glial–glial communication, state transitions, and their temporal relationship to neurodegeneration. Moreover, the lack of experimental models explicitly designed to interrogate glial biology continues to limit translational progress. Addressing these challenges will be essential to reposition glial cells as central drivers of retinal disease rather than secondary responders. A strategic shift toward glia-centered models, integrative multi-omics analyses, and human-relevant systems holds promise for advancing biomarker discovery and developing targeted therapeutic strategies that aim to modulate glial dysfunction and preserve vision. Related Articles | Metrics

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Beta 2-adrenergic pathway combats Alzheimer's disease: Restoring cognition and synaptic integrity Shaomin Li, Shan-Xue Jin 2026, 21 (10):  4832-4842.  doi: 10.4103/NRR.NRR-D-25-00529 Abstract ( 35 )   PDF (5898KB) ( 0 )   Save Alzheimer’s disease is typified by amyloid-beta oligomer-mediated synaptic disruption, neuroinflammation, and mitochondrial loss of function, culminating in cognitive decline. Recent evidence points toward the β2-adrenergic receptor as a target through its regulation of synaptic plasticity, neuroinflammation, and epigenetic control. Activation of β2-adrenergic receptor potentiates long-term potentiation, reverses amyloid-beta-mediated synaptic loss, and stimulates neuroprotective gene expression through cyclic adenosine monophosphateprotein kinase A-cyclic AMP response element-binding protein. Moreover, β2-adrenergic receptor suppression of histone deacetylase 2/3 promotes transcriptional reprogramming, supporting synaptic function. Beyond synaptic maintenance, activation of β2-adrenergic receptor prevents neuroinflammation by polarizing microglia toward an anti-inflammatory phenotype and augmenting amyloid-beta degradation. Additionally, mitochondrial metabolism is regulated by β2-adrenergic receptor, diminishing oxidative stress and allowing for bioenergetic resilience. Enriched environments mediate their neuroprotective effects through, in part, activation of β2-adrenergic receptor, supporting its role in promoting synaptic resilience. Pharmacological activation of β2-adrenergic receptor with specific agonists such as formoterol and clenbuterol has shown promise in preclinical models of Alzheimer’s disease by restoring cognitive function and synaptic integrity. In this review, the molecular mechanisms of β2-adrenergic receptor-mediated neuroprotection are examined, with specific emphasis on its regulation of synaptic plasticity, neuroinflammation, mitochondrial function, and epigenetic control. Due to its multi-faceted action for maintenance of neuronal health, activation of β2-adrenergic receptor is an appealing therapy for Alzheimer’s disease. Future research needs to target optimizing brain-penetrant β2-adrenergic receptor agonists and determining their longterm effects on Alzheimer’s disease pathology. Related Articles | Metrics

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Blood-based biomarkers and early diagnosis of Alzheimer’s disease. Zhikang Cui, Guixia Li, Shuyong Wei, Qian Cheng, Qian Yu, Shuai Zong, Pengfei Zhang, Hang Chen, Shuyi Yu, Shuang Wu, Ming Li, Zhiming Lu 2026, 21 (10):  4843-4853.  doi: 10.4103/NRR.NRR-D-25-00759 Abstract ( 46 )   PDF (6816KB) ( 1 )   Save Alzheimer’s disease is a common neurodegenerative disease characterized by progressive memory loss, cognitive decline, and behavioral changes. Blood-based biomarkers have recently gained significant attention due to their accessibility and cost-effectiveness. This review highlights the latest progress in multiple key areas of blood-based biomarkers for Alzheimer’s disease. For early diagnosis, blood-based biomarkers such as amyloid-β and phosphorylated tau can identify Alzheimer’s disease even before clinical symptoms emerge. Dynamic changes in blood-based biomarkers, including p-tau217 and neurofilament light chain, reflect disease progression and correlate with cognitive decline, enabling continuous monitoring of Alzheimer’s disease progression. Additionally, blood-based biomarkers such as p-tau181 and glial fibrillary acidic protein aid in differential diagnosis by distinguishing Alzheimer’s disease from other dementias such as frontotemporal dementia. Blood-based biomarkers related to nerve repair have opened up new avenues for tracking nerve regeneration and therapeutic response, especially brain-derived neurotrophic factor. Furthermore, advanced detection technologies such as single-molecule array and immunoprecipitation-mass spectrometry have significantly improved the sensitivity and specificity of blood-based biomarkers, facilitating their clinical translation. In summary, blood-based biomarkers hold strong potential to improve early diagnosis, monitor progression, differential diagnosis, and evaluate therapies in Alzheimer’s disease. This review provides a comprehensive and updated evaluation of the translational potential of blood-based biomarkers, emphasizing their practical utility in clinical settings and offering insights into future directions for large-scale application. This review emphasizes the need to prioritize the allocation of scientific resources, expedite the transition of blood-based biomarkers to clinical implementation, and ultimately achieve precise treatment of Alzheimer’s disease using these biomarkers. Related Articles | Metrics

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Therapeutic potential of astrocyte transdifferentiated neurons Xiaojun Liang, Rongxing Qin, Qingchun Qin, Wei Xu, Hongyu Xu, Xinyu Lai, Lingduo Shao, Caiqi Li, Minshan Xie, Xiaoyuan Xiong, Qi Tang, Li Chen 2026, 21 (10):  4854-4864.  doi: 10.4103/NRR.NRR-D-25-00554 Abstract ( 32 )   PDF (5146KB) ( 0 )   Save The permanent functional deficits resulting from the inability of adult mammalian central nervous system neurons to regenerate after injury present a significant clinical challenge. While traditional stem cell transplantation strategies continue to encounter ethical concerns and the risk of immune rejection, this impasse has shifted regenerative medicine research toward targeting endogenous astrocytes. Due to their intrinsic plasticity, widespread distribution throughout the central nervous system, and affinity for neurodevelopmental lineage, astrocytes are a unique target for in situ neuronal regeneration. This review systematically elucidates the core regulatory network governing astrocyte transdifferentiation, identifying 10 key signaling pathways, such as Wnt signaling pathway, that form a cascade regulatory system. Directed overexpression of transcription factors such as NeuroD1, Ascl1, or Neurog2 can directly initiate neuronal phenotypic conversion. Meanwhile, small molecule compounds such as valproic acid combined with CHIR99021 activate endogenous neurogenic programs by inhibiting the bone morphogenetic protein signaling axis. Notably, polypyrimidine tract binding protein 1 (PTB) gene silencing significantly enhances transdifferentiation efficiency by suppressing the microRNA 124/re1 silencing transcription factor (miR-124/REST) feedback loop. From a translational perspective, a multidimensional evaluation system based on morphological, molecular marker, and electrophysiological properties has demonstrated considerable therapeutic potential. In stroke models, NeuroD1-mediated transdifferentiation replenished approximately 30% of lost cortical neurons and improved motor coordination, evidenced by enhanced performance in food pellet retrieval, grid walking, and cylinder tests compared with controls. In spinal cord injury studies, SOX2-induced glutamatergic neurons moderately reduced glial scar density by about 25%, permitting regenerating axons to pass through while preserving the supportive structure of scar. In neurodegenerative contexts, PTB inhibition yielded functionally mature dopaminergic neurons and reconstructed nigrostriatal pathways in Parkinson’s disease models. In Alzheimer’s disease models, adeno-associated virus-delivered NeuroD1 induced whole-brain neural circuit remodeling, generating 500,000 new neurons widely distributed across the cortex and hippocampus, accompanied by improved cognitive performance. Current technical limitations include off-target effects of adeno-associated virus vectors, which cause nonspecific gene expression and require rigorous validation via Cre-loxP lineage tracing. Transdifferentiation efficiency is also highly influenced by regional microenvironments: gray matter astrocytes show higher conversion rates than those in white matter, and oxidative stress increases apoptosis among newly generated neurons. Clinical translation is further constrained by the safety of delivery systems and the aging tissue microenvironment, where transforming growth factor beta 1 is often elevated. Ferroptosis inhibitors have been shown to nearly double the survival rate of transdifferentiated cells, offering a novel strategy to mitigate oxidative damage. Based on current evidence, astrocyte transdifferentiation enables neural functional recovery across multiple disease models through endogenous repair mechanisms. Future advances should focus on optogenetically inducible vectors for spatiotemporal precision, non-viral delivery systems to mitigate vector-related risks, and integration of long-term safety validation in non-human primates with single-cell multi-omics technologies to facilitate the clinical translation of personalized regenerative therapies. Related Articles | Metrics

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Relationship of immune-inflammatory pathway and stress-induced depression with neural regeneration.  Qingying Yu, Zhaoyu Chen, Jing Zhang, Yu Cao, Mengjia Sun, Shuyi Ye, Yike Huang, Junchi He, Liping Wang, Kejian Li, Simeng Gu, Peng Sun, Qingjun Zhu, Fushun Wang, Ning Weng, Jason H. Huang 2026, 21 (10):  4865-4875.  doi: 10.4103/NRR.NRR-D-25-00324 Abstract ( 33 )   PDF (9648KB) ( 0 )   Save Major depressive disorder is a complex psychiatric condition characterized by mood dysregulation, cognitive impairment, and somatic symptoms. Recent studies underscore the pivotal roles of neural regeneration and inflammation in its pathophysiology. This narrative review synthesizes emerging evidence linking neuroinflammatory pathways and impaired neurogenesis in major depressive disorder. We explore mechanisms including microglial activation, kynurenine pathway dysregulation, synaptic remodeling, and gut–brain axis alterations. Special emphasis is placed on recent discoveries highlighting molecular cross-talk between immune responses and neural plasticity. By mapping these interactions, we aim to advance understanding of major depressive disorder subtypes and support the development of inflammation-targeted therapies. Related Articles | Metrics

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Neurovascular therapeutic potential of neuromodulation in Alzheimer’s disease Maria Luisa De Paolis, Claudio Zaccone, Marcello D’Amelio 2026, 21 (10):  4876-4877.  doi: 10.4103/NRR.NRR-D-25-00958 Abstract ( 36 )   PDF (1090KB) ( 1 )   Save Alzheimer’s disease (AD) has been traditionally viewed as a purely neuronal pathology, marked by synaptic loss , amyloid-β(Aβ) accumulation, tautangles , neuroinflammation, and metabolic imbalance. Over the past two decades, cerebrovascular dysfunction has emerged as both a co-initiator and an amplifier of AD pathology. Structural and functional perturbations within the neurovascular unit (NVU) — a dynamic interface of vascular, glial, and neuronal cells that coordinates cerebral blood flow (CBF), maintains blood–brain barrier (BBB) integrity, and regulates neuronal and synaptic activity —can precede overt cognitive symptoms and contribute to the collapse of cerebral homeostasis (Zlokovic et al., 2011; Luo et al., 2022). Accordingly, neurodegeneration and cerebrovasculopathy evolve in parallel and may reinforce each other, acting either independently and/or in synergy with Aβ accumulation. This is particularly evident in regions such as the brainstem, where the vascular architecture is uniquely vulnerable: paramedian perforating vessels arise directly from major arterial trunks, lack collateralization, and possess thin walls prone to hypertension-induced damage. These features expose these regions to elevated shear stress, spontaneous microbleeds and ischemic injury, contributing to their selective vulnerability in aging and dementia. In AD, such vascular fragility may underlie the early degeneration of the isodendritic core nuclei and the dysfunction of their projection fields (Zaccone et al., 2025). Related Articles | Metrics

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Regulation of neuronal transcription by RNA-binding proteins via R-loop dynamics Shruti Singh Kakan, Ximena Corso-Díaz 2026, 21 (10):  4878-4879.  doi: 10.4103/NRR.NRR-D-25-01373 Abstract ( 36 )   PDF (1908KB) ( 0 )   Save Neuronal cells require precise and stable control of gene expression throughout their extended lifespan, which presents numerous challenges for gene transcription. While traditional studies of transcriptional regulation have primarily focused on canonical DNA-binding factors, there is an increasing recognition of the role of regulatory RNAs and RNA-binding proteins (RBPs) in modulating this process. A wide repertoire of RNAs is expressed in eukaryotic cells, including many forms of non-coding RNAs that are transcribed from most genomic regions (Djebali et al., 2012). The majority of these non-coding RNAs play crucial roles in genome regulation, functioning both as products and regulators of gene transcription. Related Articles | Metrics

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Lipidome alteration as a hallmark and therapeutic target in Alzheimer’s disease Sijia He, Xianlin Han 2026, 21 (10):  4880-4881.  doi: 10.4103/NRR.NRR-D-25-00709 Abstract ( 36 )   PDF (527KB) ( 1 )   Save Alzheimer ’s disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and memory loss. Its well-established pathological features include the presence of extracellular amyloid-beta (Aβ) plaques, intracellular tau-containing neurofibrillary tangles, and neuroinflammation (He et al., 2025). While AD research over the past few decades has focused mainly on genetic and protein-centric mechanisms, a growing body of evidence points to lipids as a critical, yet previously underappreciated dimension of AD pathology. Recent advances in lipidomics emphasize that lipid dysregulation is not merely a secondary disease phenomenon, but rather a central component, and potentially a driving force of AD progression. This perspective article highlights altered lipid metabolism as both a hallmark and a promising therapeutic target for AD. Related Articles | Metrics

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Stem cell transplantation in stroke: current obstacles and future directions to improve efficacy Abdullah Md. Sheikh, Shozo Yano, Atsushi Nagai 2026, 21 (10):  4882-4883.  doi: 10.4103/NRR.NRR-D-25-01155 Abstract ( 40 )   PDF (6581KB) ( 1 )   Save Cerebral stroke, particularly the ischemic type, is one of the leading causes of disability and mortality worldwide. Alarmingly, the incidence of ischemic stroke is rising, especially among younger populations (Zhang et al., 2025). This concerning trend highlights the urgent need to develop and improve therapeutic strategies for stroke prevention and management. Current disease-modifying treatments for ischemic stroke primarily focus on restoring blood flow by dissolving the obstructing clot using enzymes such as tissue plasminogen activator or through mechanical thrombectomy. However, these interventions are limited by a narrow therapeutic time window, rendering a large proportion of patients ineligible. As a result, many stroke survivors experience long-term neurological deficits. These patients could benefit from regenerative therapies aimed at restoring damaged neural tissue. Even partial recovery could improve the quality of life of the patient group, also reduce the burden on health system. In this context, we propose a comprehensive regenerative approach for stroke using a combination therapy that includes sequential transplantation of genetically engineered, multiple cell types, along with gene therapy to promote neural differentiation. We also addressed the potential causes of poor grafting efficiency of transplanted cells and discussed strategies to overcome these challenges. This therapeutic strategy can be evaluated using animal models of stroke. We believe that such an approach could provide a more effective regenerative treatment option for stroke patients. Related Articles | Metrics

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From maintenance to modulation: Rethinking the role of DNA methyltransferase 1 in neuronal development Geraldine Zimmer-Bensch 2026, 21 (10):  4884-4885.  doi: 10.4103/NRR.NRR-D-25-01223 Abstract ( 53 )   PDF (461KB) ( 0 )   Save The study by Reichard et al. (2025), entitled “DNMT1-mediated regulation of somatostatinpositive interneuron migration impacts cortical architecture and function”, significantly advances our understanding of DNA methyltransferase 1 (DNMT1) in neural development by revealing a critical role in postmitotic SST-expressing cortical interneurons. Using conditional mouse genetics (Sst-Cre/tdTom/Dnmt1 loxP2 mice), live imaging, and functional assays, the authors demonstrate that DNMT1 regulates the expression of key transcription factors required for interneuron subtype identity and migration, such as Arx, in a DNA methylation-dependent manner at the postmitotic level. Loss of DNMT1 disrupts the directed migration of SST+ interneurons, causing premature cortical plate invasion. Notably, these alterations affect the surrounding microenvironment in a non-cell-autonomous fashion, impacting cortical progenitor proliferation and laminar organization. These alterations culminate in impaired cortical function and behavioral deficits related to neurological and neuropsychiatric diseases. Of note, the adult cortex of conditional mutants contained an increased fraction of SST+ interneurons coexpressing parvalbumin, suggesting a fate shift within this lineage. These findings not only highlight a previously underappreciated epigenetic safeguarding of interneuron trajectory and timing at the postmitotic level by DNMT1 but also open new avenues to explore how epigenetic regulators coordinate cellular interactions during corticogenesis—insights with potential relevance for neurodevelopmental disorders involving interneuron dysfunction. Related Articles | Metrics

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Overcoming diffusion limits to advance brain organoids Xuyu Qian 2026, 21 (10):  4886-4887.  doi: 10.4103/NRR.NRR-D-25-01296 Abstract ( 37 )   PDF (865KB) ( 0 )   Save Human pluripotent stem cell–derived brain organoids have become a central tool for modeling human neurodevelopment. Compared to traditional in vitro systems, brain organoids are distinguished by their ability to allow cells to self-organize and follow intrinsic developmental programs, thereby dynamically recapitulating aspects of in vivo brain development. Cerebral cortex organoids, for instance, can robustly mimic many features of human brain formation during mid-gestation. However, current methodologies remain largely restricted to modeling processes that occur prior to the late second trimester. Related Articles | Metrics

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Cerebral organoids as a platform to model prenatal exposure to drugs of abuse Louise Keegan, Kate Montwill, Ciaran Kennedy, Ciara L. McMahon, Jessica L. Davis, Keith J. Murphy 2026, 21 (10):  4888-4889.  doi: 10.4103/NRR.NRR-D-25-01200 Abstract ( 42 )   PDF (560KB) ( 0 )   Save Substance abuse is a global public health concern that, over the past decade, has increased by 23% worldwide (UNODC, 2023). The number of people who suffer from drug use disorders in 2023 was estimated to be 39.5 million, a 45% increase over the 10 years since 2013 (UNODC, 2023). Related to this increase, approximately 5% of pregnant women now report using one or more addictive substances during pregnancy, highlighting prenatal exposure to drugs like opioids, alcohol, and cocaine as a significant global health concern with serious consequences for fetal neurodevelopment and longterm mental health (NIDA, 2020). In utero exposure to drugs of abuse can alter brain development trajectories, leading to lifelong cognitive, behavioral, and psychiatric issues. Such in utero exposure is thought to disrupt early processes such as neurogenesis, gliogenesis, and cortical organization, ultimately resulting in structural and functional deficits. Until recently, progress in this research area has relied on either very limited human studies, typically involving correlative observation, or animal models. These studies are constrained by ethical considerations and interspecies differences, particularly relating to brain complexity and developmental timing. Related Articles | Metrics

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Advances and unmet needs in fluid and tissue biomarkers in Parkinson’s disease Ravi Rajmohan, Claire Henchcliffe 2026, 21 (10):  4890-4891.  doi: 10.4103/NRR.NRR-D-25-01239 Abstract ( 45 )   PDF (1308KB) ( 0 )   Save Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world and is increasing in prevalence. However, with multiple known risk factors and shortcomings in understanding the multifaceted aspects of this disease, there are as yet no cures and no established disease-modifying interventions. Historically, insights on pathogenesis have primarily come from autopsy studies, and one concern is that the pathological diagnosis does not always correspond to the clinical diagnosis (Hughes et al., 1992). This greatly limits our ability to investigate critical aspects of how the disease forms and progresses during life. In turn, this affects multiple aspects of care and research, including not only diagnosis, but appropriate subtyping that would be clinically meaningful, stratification for clinical trials, and providing optimal outcome measures for target engagement and treatment efficacy. Related Articles | Metrics

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Promising biomarkers for mild cognitive impairment and Alzheimer’s disease: Levels of soluble endothelial glycocalyx products Carmela Rita Balistreri, Roberto Monastero 2026, 21 (10):  4892-4893.  doi: 10.4103/NRR.NRR-D-24-01033 Abstract ( 33 )   PDF (1534KB) ( 0 )   Save A previous study has described a strong relationship between cardio- and cerebrovascular risk factors and the onset and progression of cognitive impairment (CI), and Alzheimer’s disease (AD), although their pathophysiology remains not completely understood (Balistreri, 2021). Consequently, our group has recently described the crucial role of the endothelium dysfunction, as well as of its dysfunctional endothelial glycocalyx (eGCX) and the related cellular and molecular mechanisms, in the onset of neurological pathologies, including stroke and AD (Balistreri et al., 2024; Balistreri and Monastero, 2025). The endothelium is not only the essential element of the cardiovascular system, but it also constitutes the essential component of any tissue in the human body, including the neurovascular unit and the brain–blood barrier (Balistreri and Monastero, 2023). In this case, their dysfunction triggers brain inflammation and the consequent pathological mechanisms linked to the onset and progression of CI and AD (Balistreri and Monastero, 2023). Therefore, the impact of eGCX dysfunction in the onset and progression of these diseases has also become of growing interest. The dysfunction of eGCX is characterized by its degradation, as shown by the high systemic levels of eGCX shedding products also described in AD (Balistreri et al., 2024; Balistreri and Monastero, 2025). However, data on this topic are still limited and mainly based on pre-clinical studies. Therefore, in this pilot study, we assessed whether the degradation of eGCX and endothelial dysfunction characterize AD, and in its prodromal phase, the so-called mild cognitive impairment (MCI). For this purpose, we quantified the systemic levels of certain eGCX degradation products and other molecules related to both eGCX and endothelium dysfunction, including Elabela-54, -21, and -32, syndecans (SDC) 1-4, thrombomodulin (CD141), and vascular endothelial growth factor (VEGF) in subjects with MCI and AD compared with healthy controls (HC). Related Articles | Metrics

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Retina-on-a-dish: A translational platform for tauopathy and retinal neurodegeneration Chiara D’Antoni, Lorenza Mautone, Ylenia Gigante, Anna Mirone, Silvia Di Angelantonio 2026, 21 (10):  4894-4895.  doi: 10.4103/NRR.NRR-D-25-01268 Abstract ( 31 )   PDF (730KB) ( 0 )   Save The intersection of retinal and neurodegenerative disease has drawn increasing attention, revealing the retina not only as a passive bystander but also as an active participant in central nervous system (CNS) pathology. Tauopathies such as Alzheimer’s disease (AD) and frontotemporal dementia are characterized by intracellular tau accumulation and synaptic dysfunction—hallmarks that have been observed in the retina of patients and animal models. Amyloid-beta (Aβ) pathology, another defining feature of AD, has similarly been detected in retinal tissues (Gupta et al., 2021; Gaire et al., 2024; Davis et al., 2025). This convergence supports a growing paradigm in which the retina serves as both a surrogate marker and a mechanistic substrate for CNS disease progression. Induced pluripotent stem cell (iPSC)-derived retinal systems, including 2D retinal neurons, 3D retinal organoids, and iPSC-derived retinal pigment epithelium, are redefining how we model neurodegeneration. These human-based platforms offer direct access to disease-relevant phenotypes, genetic precision, and the possibility of patient-specific studies. This article explores how these models illuminate taudriven pathology, enable mechanistic dissection, and hold promise for therapeutic and biomarker development in neurodegenerative and retinal diseases. Related Articles | Metrics

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Targeting interleukin-6 trans-signaling to improve post-stroke inflammation: A precision immunotherapy perspective Kate Mendoza, Dustin T. Nguyen, Anjali Chauhan 2026, 21 (10):  4896-4897.  doi: 10.4103/NRR.NRR-D-25-01158 Abstract ( 37 )   PDF (897KB) ( 0 )   Save Recognizing stroke recovery through an immunological lens: Stroke has traditionally been viewed as an acute neurological event resulting from vascular occlusion and subsequent neuronal death. However, mounting evidence now supports a broader perspective: stroke triggers a dynamic neuroinflammatory response that begins within hours of injury and can persist through the subacute and chronic phases. These sustained immune responses play a critical role in shaping long-term recovery. Related Articles | Metrics

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From animal models to metabolic interventions: Lessons from the Wobbler mouse Veronika Matschke 2026, 21 (10):  4898-4899.  doi: 10.4103/NRR.NRR-D-25-01456 Abstract ( 38 )   PDF (2725KB) ( 0 )   Save Motor neuron diseases such as amyotrophic lateral sclerosis (ALS) remain largely incurable, with limited therapeutic options and only modest clinical benefits from currently approved drugs. Experimental models have been instrumental in shaping our understanding of disease mechanisms, yet translation into effective therapies has been challenging. Among these models, the Wobbler mouse, although less frequently employed than superoxide dismutase 1 (SOD1) transgenics, offers unique insights into motor neuron degeneration driven by disrupted intracellular trafficking and metabolic stress. Related Articles | Metrics

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Crossroad of motor neuron disease and dementia: Insights from TDP-43 RNA-binding deficiency Molly Magarotto, Han-Jou Chen 2026, 21 (10):  4900-4901.  doi: 10.4103/NRR.NRR-D-25-01285 Abstract ( 38 )   PDF (598KB) ( 0 )   Save With our ever-increasing aging population, agerelated health issues are becoming one of the greatest sociological and economic pressures on society. This is particularly the case for neurodegenerative diseases that are estimated to affect over 1 in 3 people globally without effective treatment so far. Neurodegenerative disorders are broadly characterized by the gradual deterioration and death of neurons in the brain and/or spinal cord that leads to irreversible damage to the nervous system. Depending on the types of neurons and brain region affected, neurodegenerative diseases manifest as motor disruptions such as Huntington’s disease, amyotrophic lateral sclerosis (ALS), and Parkinson’s disease to dementias such as Alzheimer’s disease and frontotemporal dementia (FTD). All neurodegenerative diseases are associated with aberrant protein accumulation, which contributes to neuron toxicity and disease development. However, the mechanisms involved in the selective vulnerability for different types of neurons driving various clinical displays remain unclear. Related Articles | Metrics

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A serotonergic perspective on depression in Parkinson's disease: From synaptic disruption to network failure Lluis Miquel-Rio, Judith Jericó-Escolar, Analia Bortolozzi 2026, 21 (10):  4902-4903.  doi: 10.4103/NRR.NRR-D-25-01322 Abstract ( 32 )   PDF (6832KB) ( 0 )   Save For decades, the clinical identity of Parkinson’s disease (PD) has been anchored to its motor symptoms, such as tremor, rigidity, and bradykinesia, which arise from the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. However, for many patients, the most debilitating aspects of the disease are psychological and emotional rather than physical. Depression, in particular, is one of the most common and impactful non-motor neuropsychiatric symptoms, affecting up to 50% of patients with PD, often emerging years before the first signs of motor impairment (Poplawska-Domaszewicz et al., 2024). The prodromal depression is not merely a reaction to a debilitating diagnosis; rather, increasing evidence suggests that it is an integral part of the underlying neurobiology of the disease. The pioneering work of Halliday et al. (1990) and, subsequently, the pathological staging model proposed by Braak et al. (2003) more than two decades ago provided the first anatomical clue, demonstrating that the accumulation of aggregated α-synuclein (α-syn) protein, the hallmark pathology of PD, begins in the lower brainstem and affects the serotonergic (5-HT) raphe nuclei long before reaching the substantia nigra pars compacta. Understanding the consequences of early disruption of the 5-HT system is essential for improving quality of life and developing therapies that treat the whole patient, not just their motor deficits. Related Articles | Metrics

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Small-molecule TREM2 agonists: From artificial intelligence driven discovery to therapeutic application in Alzheimer's disease Sungwoo Cho, Moustafa Gabr 2026, 21 (10):  4904-4905.  doi: 10.4103/NRR.NRR-D-25-01478 Abstract ( 29 )   PDF (518KB) ( 0 )   Save The Alzheimer’s disease (AD) therapeutic landscape is evolving rapidly. While anti-amyloid antibodies have achieved regulatory approval, their incremental clinical benefits have intensified interest in neuroinflammation as a complementary therapeutic axis. Triggering receptor expressed on myeloid cells 2 (TREM2) represents a particularly attractive microglial target, given that loss-offunction variants confer a three-fold elevation in AD risk. Although TREM2 antibodies have shown promise in preclinical studies, clinical translation is hindered by fundamental limitations: restricted blood–brain barrier (BBB) penetration (< 0.1%), prohibitive annual costs exceeding $100,000, and pharmacokinetic inflexibility that precludes dose adjustment. Here, we examine how artificial intelligence (AI)-assisted approaches have enabled the discovery of small molecule TREM2 agonists and their implications for AD treatment. Related Articles | Metrics

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Potential roles of aspartic acid D-isomerization in proteins implicated in the pathogenesis of Alzheimer's disease Genta Ito, Naoko Utsunomiya-Tate 2026, 21 (10):  4906-4907.  doi: 10.4103/NRR.NRR-D-25-01311 Abstract ( 44 )   PDF (478KB) ( 1 )   Save Non-enzymatic isomerization of aspartic acid residues in proteins associated with Alzheimer’s disease: Proteins are composed of L-amino acids following ribosomal translation. However, if they remain unmetabolized for an extended period, some residues (particularly aspartic acid [Asp]) undergo isomerization to the D-form. This process begins with nucleophilic attack (by the nitrogen atom of the amide group of an adjacent residue) on the side-chain carboxy group of an Asp residue. This forms a fivemembered L-succinimide intermediate, which has two carbonyl carbons and can transform back to an L-Asp residue or isomerize into an L-isoAsp residue. The chiral center of the L-succinimide intermediate can easily invert to form a D-succinimide intermediate via keto-enol tautomerization. This D-succinimide intermediate then cleaves to yield a D-aspartic acid (D-Asp) or D-isoaspartate (D-isoAsp) residue. Related Articles | Metrics

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Recognizing Alzheimer’s disease and Parkinson’s disease as astrogliopathies Woojin Scott Kim, Onur Tanglay, YuHong Fu 2026, 21 (10):  4908-4909.  doi: 10.4103/NRR.NRR-D-25-01452 Abstract ( 34 )   PDF (494KB) ( 0 )   Save Astrocytes are the largest and most diverse glial cells in the central nervous system (CNS), with the main functions of providing support, nourishment and protection for neurons, the cells responsible for processing and transmitting information. Mounting evidence indicates that astrocytes are more than just support cells for neurons; they play complex and diverse roles that are essential for the homeostatic maintenance of the brain and spinal cord, with a key role as responders to pathological changes. As such, in recent years, there has been a dramatic increase in the interest of astrocytes in the pathogenesis of neurodegenerative diseases, Alzheimer’s disease (AD), and Parkinson’s disease (PD). Astrogliopathy is defined as pathological alterations in astrocytes, encompassing structural, molecular, or functional abnormalities that disrupt their normal roles in CNS homeostasis. These abnormalities include astrocyte reactivity, i.e. astrogliosis, degeneration, loss of supportive functions, metabolic dysregulation, impaired neurotransmitter clearance, disrupted blood-brain barrier interactions, and aberrant inflammatory signaling. Now, astrogliopathy is recognized to be a major player in both AD and PD pathogenesis. Understanding the relationship between astrocytic molecules and the accumulation of pathogenic proteins amyloid-β (Aβ) and α-synuclein will identify previously unrecognized pathways and targets, opening up new strategies for the therapeutic treatment of AD and PD, respectively. Related Articles | Metrics

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Neuroregenerative implications of dimethylglyoxal (diacetyl): A reactive metabolite in diabetes and hyperglycemic stroke Julica Inderhees, Riccardo Costalunga, Markus Schwaninger 2026, 21 (10):  4910-4911.  doi: 10.4103/NRR.NRR-D-25-00279 Abstract ( 35 )   PDF (502KB) ( 0 )   Save Dicarbonyls are biologically active compounds characterized by the presence of two adjacent carbonyl groups within the same molecule. This unique structure determines their high reactivity, presenting the basis of their biological activity. Dicarbonyls can form glycation adducts with proteins, lipids, and nucleic acids, which is why they have gained attention in diabetes research in recent years. Non-enzymatic glycation reactions occur in various tissues, leading to the formation of advanced glycation end products (AGEs) and modifications that can alter the function of the affected biomolecules. In individuals with diabetes, elevated blood glucose levels lead to increased dicarbonyl production, contributing to complications associated with the disease. The most prominent and frequently investigated representatives of the dicarbonyl group are 3-deoxyglucosone, glyoxal, and methylglyoxal. These compounds and their respective AGEs have been associated, among others, with peripheral neuropathy, nephropathy, and retinopathy (Singh et al., 2001). AGEs are known to promote inflammatory processes and oxidative stress by binding to the receptor for AGEs (RAGE), which exacerbates metabolic dysfunction in diabetes. Related Articles | Metrics

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Compact transcriptional activators: Therapeutic gene regulation in ocular disease Zhiquan Liu, Lauren Y. Chuu, Siyu Chen, Yang Sun 2026, 21 (10):  4912-4913.  doi: 10.4103/NRR.NRR-D-25-01001 Abstract ( 33 )   PDF (1027KB) ( 0 )   Save Vision loss from ocular diseases affects millions worldwide and represents a significant challenge to global health. One of these conditions, retinitis pigmentosa (RP), comprises a heterogeneous group of inherited retinal disorders caused by mutations in a wide array of genes. Although substantial progress has been made in elucidating the molecular causes of RP and related inherited retinal diseases, effective therapies remain limited, particularly for monogenic inherited forms (Tsang and Sharma, 2018). The clinical development of several adeno-associated virus (AAV)-based gene augmentation therapies is advancing; some have gained regulatory approval, including Luxturna for RPE65-associated retinal dystrophy (Ng et al., 2024). The eye presents several advantages as a target organ for gene therapy; it is immuneprivileged, anatomically accessible, and amenable to longitudinal monitoring through imaging and functional testing (Ng et al., 2024). These features position the eye as a model system for implementing novel genetic therapies, including gene editing and transcriptional modulation. However, current gene augmentation may be limited by the lack of regulatory elements. To broaden therapeutic strategies beyond traditional gene augmentation, especially for conditions driven by gene loss-of-function or haploinsufficiency, innovative approaches such as endogenous gene activation are urgently needed. Related Articles | Metrics

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Digital neuroplasticity modulation of the brain-immune axis: Translational strategies for neurodegenerative, psychiatric, and aging-related conditions Merav Catalogna, Amir Amedi 2026, 21 (10):  4914-4915.  doi: 10.4103/NRR.NRR-D-25-01728 Abstract ( 34 )   PDF (546KB) ( 0 )   Save The brain–immune axis: The dynamic interplay between neural and immune systems is emerging as a fundamental regulator of cognitive processes, affective balance, and resilience to pathological challenges (Castellani et al., 2023). Although these systems detect and respond to distinct types of stimuli, their domains of perception and response substantially overlap. The nervous system primarily encodes physical and sensory stimuli, such as light, sound, temperature, and mechanical pressure, while the immune system detects molecular cues, including pathogens, cytokines, and endogenous danger signals. Together, both systems integrate biochemical, circadian, metabolic, and stress-related inputs to maintain adaptive and coordinated responses to internal and external perturbations (Leunig et al., 2025). Related Articles | Metrics

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Emerging roles of micronuclei: Neuronal micronuclei regulate microglial properties Chihiro Maeda, Fuminori Tsuruta 2026, 21 (10):  4916-4917.  doi: 10.4103/NRR.NRR-D-25-01470 Abstract ( 32 )   PDF (470KB) ( 0 )   Save Microglia are the resident immune cells of the brain, playing indispensable roles in maintaining c e rebr a l homeostas i s f rom embr yoni c development through aging (Prinz et al., 2019). Beyond their classical immune functions, microglia are now recognized as active participants in a wide range of processes, including synaptic pruning, clearance of apoptotic neurons, neurogenesis, and synaptogenesis (Borst et al., 2021). Recent fate mapping analyses have identified that microglia originate from the yolk sac and migrate into the brain primordium (Ginhoux et al., 2010). After migration, microglia colonize the embryonic brain primordium, proliferate before and after birth, and subsequently persist as long-lived selfrenewing cells within the central nervous system (Barry-Carroll et al., 2023). Once established, they undergo context-dependent state transitions characterized by distinct transcriptional profiles, thereby acquiring diverse properties and functions (Masuda et al., 2020). Recent advances in singlecell transcriptomics and in vivo imaging have further revealed remarkable heterogeneity among microglial populations. Due to this unexpected complexity, the definition of microglial heterogeneity is currently under discussion (Paolicelli et al., 2022). These specialized populations exhibit unique anatomical niches and functional repertoires, which contribute to immune surveillance, vascular integrity, and the maintenance of the blood–brain barrier. Although this diversity is thought to be shaped by a variety of signals within the brain environment, the key factors underlying such heterogeneity have remained elusive. Recently, we discovered novel mechanisms underlying the regulation of microglial properties by micronuclei (MNs) (Yano et al., 2025). In this perspective, we present our findings demonstrating that MNs act as potential mediators of neuron-to-microglia communication and consequently regulate microglial diversity. Related Articles | Metrics

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Ocular-brain co-immunotherapy targeting β-amyloid in Alzheimer’s disease: challenges and promising therapeutic avenues Xiaohong Xiang, Yong Tang, Linlin Song, Zhuohan Li, Betty Yuen Kwan Law 2026, 21 (10):  4918-4919.  doi: 10.4103/NRR.NRR-D-25-01399 Abstract ( 32 )   PDF (2623KB) ( 1 )   Save Alzheimer’s disease is an ocular-brain comorbidity: Alzheimer’s disease (AD) is a leading neurodegenerative disorder affecting the central nervous system (CNS), clinically characterized by progressive cognitive decline, neuropsychiatric disturbances, and memory deficits. Around 60%–70% of dementia cases are due to AD, making it the most prevalent form. Current estimates suggest that approximately 50 million individuals globally are affected by AD, and the number of dementia patients is expected to rise to 139 million in 2050, with the cost of care projected to increase to nearly $1 trillion (Guo et al., 2024). The pathological hallmarks of AD predominantly consist of senile plaques, resulting from the accumulation of amyloid-beta (Aβ), and neurofibrillary tangles, arising from the hyperphosphorylation of tau protein. These features are accompanied by neuroinflammation, synaptic damage, and neuronal loss. AD is an ocular-brain comorbidity. During embryogenesis, both the retina and the brain develop from the neuroectoderm, resulting in shared anatomical, physiological, and embryological characteristics, including similarities in cell types, vasculature, and immune responses. The retina maintains structural and functional connections with the brain via the optic nerve, which links to the thalamus, optic radiation, and visual cortex. The deposition of Aβ has been observed in the postmortem eyes of AD patients and in the eyes of animal models of AD (Gaire et al., 2024). Aβ predominantly accumulates along blood vessels in the inner retinal layers, optic nerve axon bundles, meningeal lymphatic vessels of the optic nerve, and periorbital lymphatic vessels (Cao et al., 2024). Retinal Aβ is likely to originate from the brain rather than local retinal metabolism (Cao et al., 2024). Notably, Aβ can migrate from the brain to the eye within 60 minutes. The proposed mechanisms for the transport of Aβ from the brain to the eye encompass several pathways: (1) Aβ transportation along the subarachnoid space and the optic nerve sheath, with entry into the optic nerve axons via perivascular spaces; (2) axonal transport within the optic nerve directed toward the proximal optic nerve; and (3) diffusion through the perivascular spaces of the central retinal artery into the retina (Cao et al., 2024). The clearance of Aβ in the eye involves multiple processes: (1) Aβ uptake by retinal ganglion cells, followed by axonal transport through the lamina cribrosa and subsequent clearance via the meningeal lymphatic vessels of the optic nerve sheath and periorbital lymphatics; (2) glymphatic clearance facilitated by aquaporin-4 along the perivascular spaces; (3) phagocytosis and degradation by glial cells, including microglia and astrocytes; and (4) efflux across the blood–retina barrier into the systemic circulation for peripheral metabolism. The efficiency of Aβ clearance is modulated by various factors, including the cranio-ocular pressure gradient, expression levels of aquaporin-4, exposure to light, and the administration of cycloplegic agents. Related Articles | Metrics

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Targeting autophagy for postsynaptic organization and cognitive rescue in fragile X syndrome Cameron Keyser, Samantha J. Richardson, Jingqi Yan 2026, 21 (10):  4920-4921.  doi: 10.4103/NRR.NRR-D-25-01685 Abstract ( 52 )   PDF (12292KB) ( 0 )   Save Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the leading monogenic cause of autism, accounting for 1%–6% of all autism cases in U.S. (Richter et al., 2015; Berry-Kravis et al., 2018; Hagerman and Hagerman, 2022). Patients with FXS exhibit complex and debilitating neurological phenotypes, including impaired cognition and soci a l interactions, hyperactivity, attentional deficits, seizures, sleep disorders, and hypersensitivity (Berry-Kravis et al., 2018; Hagerman and Hagerman, 2022). FXS is caused by an expansion of a CGG trinucleotide repeat within the fragile X messenger ribonucleoprotein 1 (Fmr1) gene, leading to transcriptional silencing of Fmr1 (Berry-Kravis et al., 2018; Hagerman and Hagerman, 2022). Fragile X Messenger Ribonucleoprotein (FMRP), the protein encoded by Fmr1, is an RNAbinding protein that controls the localization, stability, and translation of numerous RNAs essential for synaptic development, plasticity, and architecture (Richter et al., 2015). Decades of research have revealed that loss of FMRP causes synaptic deficits through multiple mechanisms, including exaggerated metabotropic glutamate receptors signaling, elevated translation of synaptic proteins, hypoactivity of inhibitory neurons, dysregulation of presynaptic plasticity, dysfunctional synaptic mitochondria, altered potassium channels, insufficient synaptic elimination, and downregulated autophagy (Berry-Kravis et al., 2018; Yan et al., 2018; Hagerman and Hagerman, 2022; Guo et al., 2023). Related Articles | Metrics

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Breaking the age-related redox spiral for regeneration Gregory J. Brewer, Bethany Cheung 2026, 21 (10):  4922-4923.  doi: 10.4103/NRR.NRR-D-25-01439 Abstract ( 34 )   PDF (423KB) ( 0 )   Save Aging neurons do not fail randomly; rather, they enter a self-reinforcing redox spiral, rooted in metabolic responses to their environment, which diminishes their bioenergetic capacity. While pH measures proton donor potential, the redox state reflects electron donor potential, providing oxidative (e.g., NAD+) or reductive (NAD(P)H) power for numerous biochemical reactions. The decline in neuronal energy is orchestrated by mitochondrial checkpoints, transcriptional and post-transcriptional changes (Kumar et al., 2018), and proteostatic stress, all contributing to reduced synaptic resilience. Flux-control experiments highlight bottlenecks in the mitochondrial respiratory chain, particularly substrate-limited complex I and diminished capacity at complex IV (Jones and Brewer, 2010), resulting in increased electron leak, a more oxidized NAD+/nicotinamide adenine dinucleotide (NADH) and glutathione disulfide/glutathione (GSH) state, and a more oxidized quinone pool. Both young and old cortical neurons can increase respiration if provided with excess mitochondrial substrates, but old neurons are more sensitive to inhibition at complex IV. The decreased capacity for adaptive energy generation and electron transport through complex IV compared to young neuronal mitochondria likely results from regulatory nitrosylation by nitric oxide synthase (Torres et al., 1998). Importantly, aged neurons are especially dependent on endogenous substrate availability at complex I, suggesting that a shortage of NADH redox equivalents is a key constraint. This promotes glycolytic and epigenetic compensation (Walker et al., 2013), activating redox-sensitive programs that lock in an oxidative shift. Over time, the ability of the system to revert to a reduced, energy-efficient state narrows, making neurons vulnerable under metabolic stress and priming Alzheimer’s disease (AD)-related pathologies. This constraint is exacerbated in AD by decreased activity of dehydrogenases within the Krebs cycle that would lessen NADH production from NAD (Bubber et al., 2005). Related Articles | Metrics

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Post-stroke rehabilitative mechanisms in individualized fatigue level–controlled treadmill training in rats  Yuchen Xu, Yulong Peng, Yuanfa Yao, Xiaoman Fan, Minmin Wang, Feng Gao, Mohamad Sawan, Shaomin Zhang, Xiaoling Hu 2026, 21 (10):  4924-4932.  doi: 10.4103/NRR.NRR-D-25-00123 Abstract ( 42 )   PDF (6983KB) ( 2 )   Save Clinically, individualized training improves post-stroke motor function rehabilitation efficiency. However, the mechanisms underlying how individualized training facilitates recovery remain relatively unclear. Here, we explored the cortical and corticomuscular rehabilitative effects of post-stroke motor function recovery during individualized training using a rat model of intracerebral hemorrhage. Forced training or individualized fatigue-controlled training was provided from days 2 to 14 post-stroke. The fatigue-controlled training group exhibited superior motor function recovery and less central fatigue compared with the forced training group. Electroencephalograph power spectrum density slope analysis demonstrated better inter-hemispheric balance in the fatigue-controlled training group than in the forced training group. Directed corticomuscular coherence analysis indicated that training-induced fatigue led to a short-term downregulation of descending directed corticomuscular coherence and an upregulation of ascending directed corticomuscular coherence. In the long term, excessive fatigue hindered the recovery of descending control in the affected hemisphere. In conclusion, the individualized strategy of peripheral fatigue-controlled training achieved better motor function recovery, which may be attributed to the mitigation of central fatigue, optimization of inter-hemispheric balance, and enhancement of descending control in the affected hemisphere. This is the first study to investigate the mechanisms underlying individualized rehabilitative effects at the cortical and corticomuscular levels. Our findings suggest that personalized training protocols that are tailored to manage fatigue levels may substantially enhance post-stroke motor efficiency. They also provide a mechanistic foundation for developing fatigue-monitored, individualized rehabilitation programs in clinical practice. Related Articles | Metrics

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Far-infrared irradiation restores mitochondrial dynamics to ameliorate ischemic stroke Wanyu Wu, Yuping Wang, Bo Qin, Xiongfei Xu, Yuanqing Qu, Nick Wang, Wuyan Zheng, Xiaoyun Yun, Betty Yuen-Kwan Law, Jianfeng Sun, Wei Zhang, Chang Chen, Vincent Kam-Wai Wong 2026, 21 (10):  4933-4944.  doi: 10.4103/NRR.NRR-D-25-00399 Abstract ( 38 )   PDF (51202KB) ( 6 )   Save Far-infrared irradiation exhibits promise in chronic diseases, and its role in ischemic stroke  specifically in modulating mitochondrial dynamics remains unknown. This study explored the neuroprotective effects of far-infrared irradiation using a rat middle cerebral artery occlusion model and oxygen-glucose deprivation-injured neuronal cells. In middle cerebral artery occlusion rats, daily 30-minute far-infrared irradiation treatment reduced infarct volume, alleviated cerebral edema, and improved neurological function. Proteomic analysis identified far-infrared irradiation-mediated upregulation of eight proteins, including the mitochondrial fusion regulator optic atrophy 1. In oxygen-glucose deprivation-exposed cells, far-infrared irradiation restored mitochondrial membrane potential, and enhanced fusion via optic atrophy 1 induction. Mechanistically, far-infrared irradiation stabilized mitochondrial dynamics by boosting optic atrophy 1 expression, thereby reducing oxidative stress and maintaining energy production. Optic atrophy 1 knockdown partly abolished the protective effects of far-infrared irradiation therapy. These results establish far-infrared irradiation as a non-pharmacological intervention targeting mitochondrial redox homeostasis in ischemic stroke, offering a novel therapeutic avenue for cerebrovascular disorders. Related Articles | Metrics

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Dynamic structural connectivity changes in cortical and cortico-striatal strokes in mice Fatemeh Mahani, Aref Kalantari, Michael Diedenhofen, Claudia Green, Dirk Wiedermann, Gereon R. Fink, Mathias Hoehn, Markus Aswendt 2026, 21 (10):  4945-4953.  doi: 10.4103/NRR.NRR-D-25-00491 Abstract ( 41 )   PDF (3615KB) ( 1 )   Save Beyond immediate neuronal damage, functional and structural connectivity is altered brain-wide with implications for functional deficits and recovery in stroke. It remains unclear, however, if the level of axonal damage, as well as compensatory plasticity, i.e., axonal sprouting and remyelination, depend on the lesion size and topology. This study compared two different stroke models in adult male mice, with the aim of uncovering the dynamics in white matter changes. Repetitive diffusion magnetic resonance imaging was acquired over 4 weeks post photothrombotic cortical (1.41% ± 0.92% of brain volume) and middle cerebral artery occlusion cortico-striatal (11.53% ± 2.8% of brain volume) strokes. Structural connectivity changes were mapped over time at the whole-brain level. We quantified inter- and intra-hemispheric seed strength changes over time, with seed strength reflecting how strongly each region was connected to the rest of the brain. Differences between groups and time points were assessed using a mixed model corrected for multiple comparisons. The results showed that large cortico-striatal lesions led to increased structural connectivity in sensorimotor regions, whereas small cortical lesions induced asymmetric connectivity changes: an increase extending globally from the ischemic hemisphere and a decrease expanding globally from the healthy hemisphere. These findings highlight that stroke severity and lesion size significantly affect the temporal dynamics and spatial distribution of connectivity disruptions, emphasizing the need for targeted monitoring of neural changes post-stroke. Related Articles | Metrics

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Multi-omics prediction of key proteases regulating scar formation and neural repair after spinal cord injury Huan Jian, Jiahao Ren, Jiawei Du, Kailin Wu, Shen Liu, Yuanting Zhao, Hengxing Zhou, Shiqing Feng 2026, 21 (10):  4954-4964.  doi: 10.4103/NRR.NRR-D-25-01391 Abstract ( 62 )   PDF (47680KB) ( 3 )   Save Neurological injury is often accompanied by extensive infiltration of macrophages along with activation of fibroblasts and endothelial cells. The activity of these cells is associated with elevated levels of various proteases, which contribute to the hydrolysis of multiple proteins, disrupt the extracellular matrix, and further promote the migration of immune cells into uninjured neural tissue. In this study, we combined single-cell sequencing with bulk RNA sequencing data from spinal cord injury to identify up-regulated protease-related differentially expressed genes post-injury. Using gene set variation analysis, least absolute shrinkage and selection operator regression, and random forest methods, we identified adamalysins, serine proteases, and matrix metalloproteinases as key protease types. Weighted gene co-expression network analysis combined with machine learning algorithms helped predict critical protease genes involved in spinal cord injury. Immune infiltration and single-cell analyses were applied to identify cell types enriched in proteases and their spatial localization. Molecular docking and in vivo and in vitro assays using a mouse model of spinal cord injury were used to validate potential drug interactions. We identified Mmp12 and Adam17 as key effectors regulating injury progression, and determined that macrophages, fibroblasts, and monocytes are the primary cells mediating the functions of core proteinases after injury. Subsequent in vivo and in vitro experiments demonstrated that selective inhibition of key protease activity with marimastat reduced axonal demyelination and fibrous scar formation after spinal cord injury, thereby promoting the recovery of neurological function. Our study identified the key proteases that regulate spinal cord injury repair along with their mechanisms of action, and verified that inhibiting these proteases effectively alleviates scar formation and inflammatory cell infiltration, providing novel therapeutic targets for the treatment of spinal cord injury.  Related Articles | Metrics

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M1 macrophage-derived CXCL12 drives neurogenic heterotopic ossification following spinal cord injury Yulei Xie, Yaomin Luo, Xin Chen, Yinxu Wang, Wei Song, Hua Ling 2026, 21 (10):  4965-4977.  doi: 10.4103/NRR.NRR-D-25-01263 Abstract ( 35 )   PDF (77892KB) ( 0 )   Save Patients with spinal cord injury frequently develop neurogenic heterotopic ossification, whose pathogenesis remains incompletely understood. Existing research models struggle to accurately simulate the complex pathological process. To establish a reliable neurogenic heterotopic ossification research model, elucidate its pathogenesis, and explore early intervention strategies, this study successfully developed a spinal cord injury-induced neurogenic heterotopic ossification mouse model. Significant ectopic bone formation, restricted hip and knee joint mobility, and motor dysfunction were observed, accompanied by elevated expression of the osteogenic markers alkaline phosphatase, runt-related transcription factor 2, sex-determining region Y-box 9, and osteocalcin . Proteomics and quantitative polymerase chain reaction analysis revealed upregulation of chemokine (C-X-C motif) ligand (CXCL)12, C-X-C chemokine receptor type 4 (CXCR4), and LYN proto-oncogene, whereas CXCL1 was downregulated in the neurogenic heterotopic ossification group. In vivo experiments confirmed abnormal accumulation of M1 macrophages in muscles surrounding early ectopic bone tissue, with markedly elevated CXCL12 expression. In vitro studies further revealed that M1 macrophages are the primary source of CXCL12 secretion, and their cell culture supernatants promote the proliferation, migration, and osteoblastic differentiation potential of bone marrow mesenchymal stem cells. Mechanistically, CXCL12 activates the phosphatidylinositol 3-kinase/protein kinase B pathway by binding to the CXCR4 receptor, thereby driving the osteogenic differentiation of bone marrow mesenchymal stem cells. These findings indicate a causal relationship between the pathological process of neurogenic heterotopic ossification following spinal cord injury and the activation of the CXCL12-CXCR4-phosphatidylinositol 3-kinase-protein kinase B signaling axis, which modulates bone marrow mesenchymal stem cell function through M1 macrophage polarization. This study reveals a key mechanism driving the osteogenic differentiation of bone marrow mesenchymal stem cells, providing new directions for early warning and targeted treatment of neurogenic heterotopic ossification following spinal cord injury. Related Articles | Metrics

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Modulation of the regenerative microenvironment within acellular nerve allografts using tacrolimus improves nerve regeneration. Jesús A. Acevedo Cintrón, Jonathon Blake Schofield, Daniel A. Hunter, Pranay Singh, Alexa M. Negrón Morales, Lauren Schellhardt, Susan E. Mackinnon, Matthew D. Wood 2026, 21 (10):  4978-4988.  doi: 10.4103/NRR.NRR-D-25-01014 Abstract ( 40 )   PDF (25477KB) ( 0 )   Save Acellular nerve allografts have been used as an alternative to reconstruct nerve gaps. However, regeneration and recovery using long acellular nerve allografts (> 3 cm) is poor in comparison to short acellular nerve allografts (< 3 cm). To understand why long acellular nerve allografts have limited regeneration, we focused on identifying differences in the microenvironment of short (2 cm) and long (4 cm) acellular nerve allografts by comparing the transcriptional profile of these acellular nerve allografts. After repairing the sciatic nerve of Lewis rats using either short or long acellular nerve allografts, we found that the proximal and mid-distal graft regions of long acellular nerve allografts are characterized by an upregulation of metabolic and immune pathways and downregulation of regenerative processes in comparison to the short acellular nerve allografts. Based on these results, we modulated the regenerative and immune microenvironment of long acellular nerve allografts using tacrolimus (FK506). Histomorphometric and muscle force analysis revealed that FK506 increases the number of axons and improves recovery of motor function across long acellular nerve allografts. Transcriptome analysis of the mid-distal graft region of long acellular nerve allografts from animals treated with FK506 revealed upregulation of regenerative pathways and downregulation of immune processes, specifically related to T cell activity. Additionally, FK506 altered the number of macrophages and Schwann cells in the long acellular nerve allografts. From the transcriptome analysis, we identified FK506 upregulates expression of Spp1 (osteopontin) which promotes regeneration of motor neurons after injury. Experiments on cultured Schwann cells revealed that FK506 increases mRNA expression of Spp1. Our data show the development of a degenerative and immune microenvironment within long acellular nerve allografts and demonstrate that FK506 can modulate this microenvironment to improve nerve regeneration across these long acellular nerve allografts. Related Articles | Metrics

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Engineered mesenchymal stem cell–derived extracellular vesicles overexpressing miR-146a alleviate neuroinflammation in Alzheimer’s disease Jia Zhang, Siqi He, Qiguo Xiao, Weijie Jiang, Bo Wang, Jing Lu, Hongfeng Gu, Yajin Liao, Zhi Wang, Ying Xu, Dan Wang, Xiaoqing Tang, Ling Qi 2026, 21 (10):  4989-4999.  doi: 10.4103/NRR.NRR-D-25-00404 Abstract ( 50 )   PDF (9579KB) ( 1 )   Save Alzheimer’s disease is an inflammatory neurodegenerative disease for which no effective clinical treatment currently exists. We have previously reported that mesenchymal stem cell–derived extracellular vesicles delay retinal degeneration by exerting anti-inflammatory effects though the miR-146a–nuclear receptor subfamily 4 group A member 3 axis; however, it remains unclear how NR4A3 drives inflammation. Herein, we engineered mesenchymal stem cell–derived extracellular vesicles overexpressing miR-146a to explore their possible neuroprotective effects and the underlying mechanisms in both cell and animal models of Alzheimer’s disease. In HT22 cells co-cultured with lipopolysaccharide-induced RAW264.7/BV2 cells, extracellular vesicles overexpressing miR-146a significantly reduced the number of apoptotic cells and inhibited proinflammatory cytokine expression, nuclear factor (NF)-κB activation, and caspase-3/apoptosis regulator BAX signaling. These effects of extracellular vesicles overexpressing miR-146a were replicated in 5×FAD mice. In addition, extracellular vesicles overexpressing miR-146a inhibited the activation of microglia and astrocytes, reduced amyloid-β and phosphorylated tau expression, lowered the number of apoptotic cells in the hippocampus, and improved the cognitive function of these Alzheimer’s disease model mice. Mechanistically, miR-146a negatively regulated the expression of nuclear receptor subfamily 4 group A member 3 and suppressed the expression of proinflammatory cytokines and nuclear factor-κB signaling. Furthermore, NR4A3 overexpression promoted nuclear factor-κB and proinflammatory cytokine expression as well as nuclear factor-κB signaling. The upregulation of NR4A3 and the inflammatory response was reversed by miR-146a overexpression. Finally, NR4A3 was identified as a transcriptional activator of nuclear factor-κB using chromatin immunoprecipitation polymerase chain reaction. Collectively, these findings indicate that extracellular vesicles overexpressing miR-146a may alleviate the progression of Alzheimer’s disease by exerting anti-inflammatory effects via the NR4A3–nuclear factor-κB axis. They are thus a potential therapeutic candidate for the clinical treatment of neurodegenerative diseases. Related Articles | Metrics

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Neurotoxicity, α-synuclein pathology, and mitochondrial dysfunction: A comparative study of different mouse models of Parkinson’s disease Xiwen Tang, Yifei He, Min Liang, Penggang Ning, Jiayin Zhao, Yunhe Zhang, Xin Yan, Ruilin Sun, Gang Wei, Ruling Shen, Fang Huang, Mei Yu 2026, 21 (10):  5000-5012.  doi: 10.4103/NRR.NRR-D-25-00648 Abstract ( 35 )   PDF (13949KB) ( 1 )   Save The causes of Parkinson’s disease are complex, and it is difficult for a single animal model to fully mimic its pathological characteristics. In this study, a comprehensive analysis of behaviors, Parkinson’s disease–like pathologies, and gene and protein expression profiles was carried out in three mouse models of disease: 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine-induced, α-synuclein (α-syn) A53T transgenic, and MitoPark, revealing both shared and model-specific pathogenic pathways to guide model selection and identify potential therapeutic targets. All three Parkinson’s disease models exhibited motor impairments, with particularly pronounced age-related decline observed in MitoPark mice. Pathologically, nigrostriatal pathway damage was observed in all models, yet with distinct patterns of glial cell activation. Sixteen-month-old α-syn A53T mice displayed a few pS129- α-syn-positive signals in the substantia nigra, while no α-syn aggregates were observed in any of the models. RNA sequencing and proteomics analysis revealed significant changes in gene and protein expression, with both unique and common features among the three models. Five common differentially expressed genes (Ifi27l2a, Ifitm3, Oasl2, Rtp4, and Ankk1) and two common differentially expressed proteins (Timm8a1 and Sephs1) were identified. Functional enrichment analysis indicated that immune responses, cytokines, and neurotransmitter transport were crucial in Parkinson’s disease pathogenesis. Notably, multiple iron-related cell damage (ferroptosis)-related differentially expressed genes were identified across all three models, while interleukin 17 pathway activation was altered in MitoPark mice. In summary, we analyzed the commonalities and specificities of pathological simulation capabilities and common disease mechanisms in different mouse models of Parkinson’s disease from multiple perspectives. Our findings offer valuable insights into the multifaceted characteristics of Parkinson’s disease and will assist in model selection for mechanistic exploration in the future.  Related Articles | Metrics

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Lycium barbarum glycopeptide protects neurons from amyloid-beta toxicity Zihang Chen, Xiao Wang, Simin Wang, Zelin Wu, Huajun Wang, Kin Chiu, Xiaofei Zheng, Kwok-Fai So 2026, 21 (10):  5013-5019.  doi: 10.4103/NRR.NRR-D-25-00501 Abstract ( 44 )   PDF (3738KB) ( 7 )   Save Oligomeric amyloid-beta deposition within neurons and its associated neurotoxicity are among the most direct indicators of the onset of Alzheimer’s disease. Investigations into strategies aimed at reducing amyloid-beta accumulation or promoting its clearance in neurons are currently being carried out. Lycium barbarum glycopeptide is rich in biologically active compounds and possesses antioxidant, anti-inflammatory, and neuroprotective properties. This study verified that the oligomer amyloid-beta1–42 induced toxic effects in mouse N2a neuroblastoma cells, resulting in elevated levels of reactive oxygen species and increased expression of the inflammatory enzyme inducible nitric oxide synthase. Lycium barbarum glycopeptide counteracted these effects by alleviating cell damage, enhancing cell viability, reducing the levels of reactive oxygen species and inducible nitric oxide synthase expression, and up-regulating the mRNA levels of antioxidant enzymes, including superoxide dismutase 1, superoxide dismutase 2, and glutathione peroxidase 4. Lycium barbarum glycopeptide also activated the phosphoinositide 3-kinase/Akt/p70S6K signaling pathway and promoted the expression of brain-derived neurotrophic factor, thus exerting neuroprotective effects. These findings indicate that Lycium barbarum glycopeptide may be a promising candidate for the treatment of Alzheimer’s disease. Related Articles | Metrics

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Targeted nanovesicular delivery of dexmedetomidine modulates microglial lysosomal function via Sirt3 signaling to ameliorate neurodegenerative pathology Yuan Zhang, Hui Jiang, Fuqing Zhang, Jinghua Liao 2026, 21 (10):  5020-5034.  doi: 10.4103/NRR.NRR-D-25-00234 Abstract ( 40 )   PDF (93237KB) ( 0 )   Save Neuroinflammation and lysosomal dysfunction in microglia are increasingly recognized as critical pathological drivers of Alzheimer’s disease, yet current anti-inflammatory or neuroprotective agents have limited brain delivery efficiency and cellular specificity. To address these challenges, this study proposes a novel nanotherapeutic paradigm based on extracellular nanovesicles (ENVs) for targeted modulation of microglial function. This research explored the potential of a novel nanotherapeutic platform involving ENVs functionalized with aptamers and encapsulating dexmedetomidine (Dex) to alleviate microglia-associated neuroinflammation in Alzheimer’s disease. The effects on microglial lysosomal function, neuroinflammation, and cognitive performance were evaluated in an Alzheimer’s disease mouse model. Cholesterol-conjugated PEG 2000 aptamers were used to modify extracellular nanovesicles derived from microglial cells. The nanovesicles (ZH-1c-ENVs) were loaded with Dex using ultrasound-assisted methods. Particle size, morphology, and drug release kinetics were characterized using dynamic light scattering and transmission electron microscopy. In vitro assays assessed microglial cell uptake and cytotoxicity, while in vivo biodistribution was evaluated in a mouse model. Proteomics, western blotting, quantitative reverse transcription-polymerase chain reaction, and immunofluorescence were employed to analyze the effects of ZH-1c-ENVs@Dex on microglial inflammation, lysosomal activity, and amyloid-beta clearance. Cognitive function improvements were assessed using the Morris water maze. ZH-1c-ENVs@Dex achieved efficient drug encapsulation and crossed the blood–brain barrier, delivering Dex selectively to microglial cells. Proteomic analysis revealed activation of the Sirtuin 3 signaling pathway, which reduced microglial inflammation and enhanced lysosomal function. These changes promoted amyloid-beta clearance in vitro and alleviated neuroinflammation in vivo. Treatment significantly improved cognitive performance in Alzheimer’s disease mice. The ZH-1c-ENVs@Dex system represents a promising nanomedicine strategy for Alzheimer’s disease therapy by modulating Sirtuin 3 activity, restoring microglial function, and improving cognitive outcomes. This study lays the groundwork for clinical translation of aptamer-modified ENVs as precision nanomedicines for neurodegenerative diseases. The ZH-1c-ENVs@Dex system integrates clinically safe components, efficiently traverses the blood–brain barrier, and selectively targets microglia, exhibiting remarkable potential for the treatment of Alzheimer’s disease and related neurodegenerative disorders. This scalable and highly biocompatible nanovesicular platform offers a clinically translatable strategy with substantial therapeutic promise for neuroinflammatory and neurodegenerative diseases. Related Articles | Metrics

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Mesenchymal stem cell–derived extracellular vesicle treatment of induced pluripotent stem cell–derived motor neurons with different amyotrophic lateral sclerosis genetic backgrounds. Suzy Varderidou-Minasian, Channa E. Jakobs, Svetlana Pasteuning-Vuhman, Lars Gal, Annabel Timmers, Maarten Altelaar, Magdalena J. Lorenowicz. Jeroen Pasterkamp 2026, 21 (10):  5035-5043.  doi: 10.4103/NRR.NRR-D-25-01790 Abstract ( 43 )   PDF (5226KB) ( 1 )   Save Motor neurons derived from induced human pluripotent stem cells offer a powerful model to study motor neuron diseases, such as amyotrophic lateral sclerosis. While widely used, our knowledge of the proteomic changes in these models is rather rudimentary. In this study, we conducted a comparative proteomic analysis of induced pluripotent stem cell–derived motor neurons carrying amyotrophic lateral sclerosis–associated mutations in C9ORF72, TARDBP, or FUS. This revealed both mutation-specific and shared proteomic signatures, unveiling common and divergent disease mechanisms. Using these new insights, we then evaluated the therapeutic potential of mesenchymal stem cell–derived extracellular vesicles. These experiments showed a functional effect of mesenchymal stem cell–derived extracellular vesicles in amyotrophic lateral sclerosis-FUS motor neurons in vitro and their ability to reverse proteomic changes more generally in motor neurons with different amyotrophic lateral sclerosis genetic backgrounds. These findings highlight key molecular pathways involved in amyotrophic lateral sclerosis at the protein level and support the potential of mesenchymal stem cell–derived extracellular vesicles as a versatile therapeutic approach. Related Articles | Metrics

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Poly(ADP-ribose) polymerase regulates transient receptor potential channel M2-dependent calpain activation in rd1 mouse retinal degeneration Jie Yan, Lei Kong, Zhijian Zhao, Qianlu Yang, Lan Wang, Qianxi Yang, Christian Harteneck, Kangwei Jiao, Zhulin Hu, François Paquet-Durand 2026, 21 (10):  5044-5050.  doi: 10.4103/NRR.NRR-D-24-01102 Abstract ( 42 )   PDF (21584KB) ( 4 )   Save Inherited retinal degeneration refers to untreatable blinding diseases characterized by progressive photoreceptor loss. Photoreceptor degeneration is often associated with an excessive activation of poly(ADP-ribose) polymerase and Ca2+-dependent calpain-type proteases. To explore the interplay between poly(ADP-ribose) polymerase and calpain activity, we employed organotypic retinal explant cultures derived from wild-type mice and from the rd1 mouse model for inherited retinal degeneration. Retinae were treated with the poly(ADP-ribose) polymerase inhibitors INO1001 or Olaparib, the poly(ADP-ribose) glycohydrolase inhibitor JA2131, or the transient receptor potential channel M2 blocker 8-Br-ADPR. Readouts included the terminal deoxynucleotidyl transferase dUTP nick end labeling assay to detect cell death, in situ activity assays for histone-deacetylases, poly(ADP-ribose) polymerase, and calpain, as well as immunostaining for activated calpain-2, and poly(ADP-ribose). Poly(ADP-ribose) polymerase, poly(ADP-ribose) glycohydrolase, and transient receptor potential channel M2 inhibition reduced calpain activity and calpain-2 activation. Poly(ADP-ribose) polymerase activity was decreased by poly(ADP-ribose) polymerase and transient receptor potential channel M2 inhibitors but not by poly(ADP-ribose) glycohydrolase inhibition. Remarkably, the poly(ADP-ribose) polymerase inhibitor INO1001 increased histone-deacetylase activity unlike any of the other compounds. When combined with the poly(ADP-ribose) glycohydrolase inhibitor JA2131, INO1001 reduced photoreceptor cell death in a synergistic fashion, although such synergy was not observed for calpain or poly(ADP-ribose) polymerase activity. Moreover, synergistic photoreceptor preservation was not observed when JA2131 was combined with the poly(ADP-ribose) polymerase inhibitor Olaparib. Overall, these results indicate that in rd1 photoreceptors, poly(ADP-ribose) polymerase controls calpain activity via poly(ADP-ribose) glycohydrolase and transient receptor potential channel M2-induced Ca2+ influx. We also characterized INO1001 as potentially more beneficial for inherited retinal degeneration treatment than Olaparib. Our study details the complexity of poly(ADP-ribose) polymerase-signaling in photoreceptors and identifies poly(ADP-ribose) glycohydrolase and transient receptor potential channel M2 as new targets for inherited retinal degeneration therapy development. Related Articles | Metrics

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The m6A writer VIRMA regulates the developmental elimination of retinal astrocytes and retinal vascular integrity maintenance. Cuiting Wu, Xiaoli Wu, Min Wu, Xidan Zhou, Jie Tu, Bin Shen, Tao Zhou 2026, 21 (10):  5052-5062.  doi: 10.4103/NRR.NRR-D-25-00295 Abstract ( 36 )   PDF (43136KB) ( 0 )   Save Proper migration and formation of the astrocyte network are essential for retinal vasculature and visual function. However, the underlying mechanisms remain incompletely understood. In the present study, we identified protein virilizer homolog VIR-like m6A methyltransferase associated (VIRMA)—the core scaffolding protein of the N6-methyladenosine (m6A) methyltransferase complex—as a novel regulator of retinal astrocytes and visual function. We demonstrated that the conditional knockout of VIRMA in retinal astrocytes impaired microglia-mediated phagocytic clearance, leading to abnormal astrocyte accumulation during postnatal development. Notably, this disruption in cellular homeostasis preceded subsequent pathological vascular remodeling. Although initial retinal vascularization appeared normal in VIRMA-deficient mice, persistent vascular plexus instability developed, ultimately leading to vessel regression and irreversible visual impairment. Mechanistically, single-nucleus transcriptomic analysis revealed that the loss of VIRMA disrupted the expression of multiple m6A-modified genes that are involved in extracellular matrix organization and angiogenesis. These molecular changes were correlated with impaired astrocyte–endothelial cell communication and contributed to the breakdown of vascular homeostasis. Collectively, our study identifies VIRMA/m6A as a novel regulator of the developmental elimination of retinal astrocytes and the maintenance of neurovascular integrity. This research provides new insights into astrocyte-related retinopathies and highlights potential therapeutic targets for vascular-associated visual disorders. Related Articles | Metrics

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Heat shock protein 40 enhances axon regeneration in a mouse model of traumatic optic neuropathy Jiaxing Wang, Ying Li, Felix L. Struebing, Sandra Jardines, Su-Ting Lin, Fangyu Lin, Eldon E. Geisert 2026, 21 (10):  5063-5070.  doi: 10.4103/NRR.NRR-D-25-00034 Abstract ( 48 )   PDF (7836KB) ( 1 )   Save Retinal ganglion cell death occurs following injury to the optic nerve either by trauma or in disease such as glaucoma, leading to severe vision loss. Recent innovations have demonstrated that optic nerve regeneration is feasible; however, the regeneration is limited. The aim of the present study is to identify genomic elements enhancing axon regeneration. We have taken a forward genetics approach using the BXD recombinant mouse strains to identify a gene that increases the extent of optic nerve regeneration. Axon regeneration was induced by knocking down Pten in retinal ganglion cells using adeno-associated virus to deliver an shRNA followed by an intravitreal injection of Zymosan with CPT-cAMP that produced a mild inflammatory response. Retinal ganglion cell axons were damaged by optic nerve crush. Following a 12-day survival period, regenerating axons were labeled by intravitreal injection of Cholera Toxin B conjugated with Alexa Fluor 647. Two days later, labeled axons within the optic nerve were examined to determine the number of regenerating axons and the distance they traveled down the optic nerve. The analysis revealed a surprising difference in the amount of axonal regeneration across all 33 BXD strains. There was a 7.5-fold difference in the number of regenerating axons and a 4-fold difference in the distance traveled by regenerating axons. These data were used to generate an interval map defining genomic loci that modulate enhanced axonal regeneration. A quantitative trait locus modulating axon regeneration was identified on Chromosome 14 (115 to 119 Mb). Within this locus were 16 annotated genes. Subsequent testing revealed that one candidate gene, Dnajc3, modulated axonal regeneration. Dnajc3 encodes heat shock protein 40 (HSP40), a molecular chaperone. Knocking down Dnajc3 in the high regenerative strain (BXD90) led to a decreased regeneration response, whereas, overexpression of Dnajc3 in a low regenerative strain (BXD34) resulted in an increased regeneration response. These findings reveal that Dnajc3 not only increases the number of regenerating axons, but also increases the distance that axons travel. The enhanced regeneration will prove to be critical for functional recovery in humans, where the distance axons travel to their targets is considerably longer than that of mice. Related Articles | Metrics

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Lycium barbarum polysaccharide as a retinoprotective agent: A meta-analysis of preclinical evidence from rodent models of retinopathy Li Jiang, Erjin Wang, Shengpeng Wang, Yitao Wang 2026, 21 (10):  5071-5080.  doi: 10.4103/NRR.NRR-D-25-00772 Abstract ( 39 )   PDF (1505KB) ( 0 )   Save Lycium barbarum polysaccharides are considered the primary active ingredient of Lycium barbarum, and their therapeutic effects on retinal diseases have been extensively described. However, a systematic review and meta-analysis of these studies have not been conducted previously. This review aims to systematically review and meta-analyze published animal studies to investigate the mechanisms of the antioxidative, anti-inflammatory, anti-apoptotic, and neuroprotective effects of Lycium barbarum polysaccharides in rodent models of retinal diseases. To objectively and quantitatively compare the efficacy of Lycium barbarum polysaccharides in rodent models of retinal disease, a systematic review was conducted to search the PubMed and Web of Science databases (from inception to July 2024) for studies conducted in animals that met all a priori inclusion criteria. The included 27 studies reported outcomes on retinal structure (outer nuclear layer thickness) or function (electroretinogram b-wave amplitude). The methodological quality, assessed using the SYRCLE bias risk assessment tool, indicated that the overall risk of bias in the included literature was predominantly moderate. The results of the meta-analysis conducted using RevMan 5.4.1 software found that Lycium barbarum polysaccharides are protective against retinal injury in animal models, as evidenced by increases in the thickness of the outer nuclear layer and b-wave amplitude. The mechanisms involved include antioxidant effects, anti-inflammation, anti-apoptosis, and modulation of glia-driven neuroinflammation. Findings from this review confirm the protective actions of Lycium barbarum polysaccharides on retinal outer nuclear layer thickness and neuronal cells in rodent models of retinal diseases and may help propose strategies for future translational research on Lycium barbarum polysaccharides.  Related Articles | Metrics