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15 July 2026, Volume 21 Issue 7 Previous Issue   

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Evolution of neutrophil extracellular traps in the pathology of stroke Wenjing Ning, Qian Wang, Yuzhen Xu 2026, 21 (7):  2685-2703.  doi: 10.4103/NRR.NRR-D-25-00364 Abstract ( 472 )   PDF (10916KB) ( 79 )   Save Stroke is a major cause of death and disability worldwide, and its pathogenesis is complex, involving multiple pathological processes, such as thrombosis, ischemia-reperfusion injury, inflammatory response, and blood–brain barrier disruption. In recent years, neutrophil extracellular traps have been found to be involved in the body’s anti-infection defense and to play an important role in stroke. Studies have shown that neutrophil extracellular traps promote thrombus expansion and neuroinflammation in ischemic stroke, and they may be involved in disease progression and recovery in hemorrhagic stroke by modulating local inflammation and influencing hematoma clearance. This review systematically summarizes the evolution and mechanism of action of neutrophil extracellular traps in stroke pathology. Reactive oxygen species drive the formation of neutrophil extracellular traps 6–24 hours after cerebral infarction. At 24–48 hours, they exacerbate vascular injury and thrombosis, at 48–72 hours, they aggravate neurological injury, and after 72 hours, neutrophil extracellular traps are involved in the disruption of the blood–brain barrier and the maintenance of the inflammatory response. During stroke development, neutrophil extracellular traps are involved in multiple pathological mechanisms after cerebral infarction. They induce vascular endothelial damage, exacerbating vascular leakage and edema, injuring neurons, inducing apoptosis, promoting thrombosis, participating in reperfusion injury, and damaging the blood–brain barrier. In hemorrhagic stroke, neutrophil extracellular traps are closely associated with hematoma clearance, early brain injury, and delayed cerebral ischemia, and can be used as a biomarker to assess disease progression and efficacy. In the acute phase of stroke, neutrophil extracellular traps mainly promote injury, and in the chronic phase, they mainly promote repair. Neutrophil extracellular traps, as an important biomarker of stroke, are closely correlated with stroke severity. Additionally, neutrophil extracellular traps play an important role in atherosclerosis and intracranial venous thrombosis. Current research has confirmed that deoxyribonuclease is a key drug for degrading neutrophil extracellular traps and has shown significant therapeutic potential. Peptidyl arginine deiminase 4 inhibitors and high mobility group box 1 antagonists effectively inhibit the formation of neutrophil extracellular traps through their own unique mechanisms. Multi-targeted intervention strategies for neutrophil extracellular traps have shown broad clinical application prospects. Neutrophil extracellular traps exhibit synergistic effects with anticoagulants and thrombolytic drugs, and interventions targeting neutrophil extracellular traps can influence the efficacy of anticoagulation and thrombolytic therapy. These findings provide a theoretical basis for developing new anticoagulation and thrombolysis strategies for stroke and improving clinical outcomes for patients. Related Articles | Metrics

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Biomarker advancements in cerebral small vessel disease: An overview Wenqian Luo, Chenhui Cao, Wenli Li, Ting Wei, Zeyu Zhao, Guanqing Wang, Xiaoli Li, Yanbin Li , Bin Liu 2026, 21 (7):  2704-2714.  doi: 10.4103/NRR.NRR-D-24-01329 Abstract ( 189 )   PDF (2139KB) ( 674 )   Save Cerebral small vessel disease is a condition caused by chronic cerebral hypoperfusion due to microvascular damage and is a major contributor to stroke and dementia. Traditionally, its diagnosis has relied primarily on neuroimaging findings. However, recent advances in the understanding of cerebral small vessel disease pathophysiology have opened new avenues for early detection and targeted therapeutic interventions. Notably, the identification and investigation of cerebral small vessel disease–related biomarkers have emerged as a promising strategy for early diagnosis. This review provides an overview of recent research on cerebral small vessel disease biomarkers, including plasma biomarkers, cerebrospinal fluid biomarkers, and genetic markers. Finally, we discuss future directions and trends in the clinical validation of these biomarkers. Related Articles | Metrics

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Advances and applications of brain organoids in central nervous system disorders: Bridging the gap from laboratory to clinic Changle Fang, Qiulin Wang, Qiuxia Xiao, Xiaoxing Cai, Ruolan Du, Lulu Xue, Xiaohe Tian, Liulin Xiong 2026, 21 (7):  2715-2730.  doi: 10.4103/NRR.NRR-D-24-01490 Abstract ( 216 )   PDF (5407KB) ( 228 )   Save Investigating the mechanisms underlying central nervous system disorders is a major scientific issue in the 21st century. However, the inaccessibility and complexity of the human brain have always represented a challenge in understanding the pathophysiology of the central nervous system. Brain organoids are self-assembled three-dimensional aggregates derived from pluripotent stem cells with cell types and structures similar to the embryonic human brain, giving them potential for investigating the atypical cellular, molecular, and genetic characteristics characteristic of central nervous system disorders. Brain organoids also provide a platform for drug screening and serve as a potential source for transplantation therapy for brain injuries. However, the broad application of brain organoids is hampered by several limitations, such as the lack of high-fidelity cell types, insufficient maturation, and considerable heterogeneity, undermining their reliability in specific applications. This review summarizes brain organoid evolution, discusses recent technological and methodological innovations, and reviews their applications in drug screening, transplantation therapy, and disease modeling, as well as clinical research progress. Additionally, we emphasize the limitations of current brain organoid research and explore the potential for advancing the technology to enhance its applicability. Related Articles | Metrics

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Intriguing role of the Golgi apparatus in astrocyte function: Implications for disorders Martina Polenghi, Elena Restelli, Elena Taverna , Laura Tapella 2026, 21 (7):  2731-2736.  doi: 10.4103/NRR.NRR-D-25-00342 Abstract ( 135 )   PDF (1860KB) ( 52 )   Save Cell function has a tight relationship with cell architecture. Distribution of proteins to the correct compartment is one of the functions of the traffic pathway through the Golgi apparatus. The others are to ensure proper protein folding, the addition of post-translational modifications, and delivering to intracellular and extracellular destinations. Astrocytes are fundamental homeostatic cells, controlling multiple aspects of the central nervous system physiology, such as ion balance, nutrients, blood flow, neurotransmitters, and responses to insults. Astrocytes are polarized cells, and, such as neurons, extensively use the secretory pathway for secreting factors and exposing functional receptors, channels, and transporters on the plasma membrane. In this review, we will underline the importance of studying the Golgi apparatus and the secretory pathway in astrocytes, based on the possible tight connection between the Golgi apparatus and astrocytes’ homeostatic function. Given the topic of this review, we will provide examples mostly about the Golgi apparatus structure, function, localization, and its involvement in astrocytes’ homeostatic response, with an insight into congenital glycosylation disorders, as an example of a potential future field in the study of astrocyte homeostatic failure and Golgi apparatus alteration. Related Articles | Metrics

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Decellularized matrix grafts and peripheral nerve regeneration Qin Zhang, Xingyu Liu, Ye Zhu, Tianmei Qian, Shanshan Wang, Meiyuan Li 2026, 21 (7):  2737-2751.  doi: 10.4103/NRR.NRR-D-25-00526 Abstract ( 199 )   PDF (25391KB) ( 63 )   Save Traditional nerve repair methods, such as autologous nerve grafting and allogeneic nerve grafting, face issues such as donor shortage, functional loss, and immune rejection. Decellularized extracellular matrix-based grafts have emerged as highly promising alternatives, capable of uniquely recreating the natural neural microenvironment, promoting host cell remodeling, and ultimately enhancing functional neural regeneration. This review comprehensively analyzes the key mechanisms of peripheral nerve injury and regeneration, focusing on contemporary therapeutic strategies for key aspects such as axonal apoptosis inhibition, enhanced intrinsic regenerative capacity, construction of regenerative microenvironment, and prevention of target organ atrophy. Findings from this review has shown that decellularized extracellular matrix grafts can promote the migration, proliferation, and differentiation of nerve cells by providing physical support, chemical signals, and mechanical stability. Decellularized extracellular matrix grafts are mainly used as nerve conduits, scaffolds, hydrogels, and 3D printing inks. Decellularized extracellular matrix grafts have demonstrated significant advantages in promoting nerve regeneration by regulating the proliferation and differentiation of Schwann cells, improving the neural microenvironment, reducing inflammatory responses, and promoting angiogenesis. Additionally, decellularized extracellular matrix grafts can serve as drug carriers, enabling the controlled release of growth factors, which further enhances nerve regeneration. However, these grafts also have some limitations, including the presence of immunogenic residues, inadequate mechanical properties, inter-batch variability, and uncontrollable degradation rates. Future research should focus on optimizing the decellularization process, enhancing the mechanical properties of decellularized extracellular matrix grafts, reducing immunogenicity, improving biocompatibility and safety, and developing new composite materials. Furthermore, exploring their application potential in complex nerve injuries, such as diabetic neuropathy, is crucial to meet the needs of peripheral nerve regeneration and repair. Related Articles | Metrics

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Phosphatase and tensin homolog: A potential target for therapeutic intervention in optic nerve regeneration Bin Tong, Yanzhuo Song, Zhengyang Li, Muhan Cai, Haodong Qi, Kangtai Su, Hong A. Xu 2026, 21 (7):  2752-2760.  doi: 10.4103/NRR.NRR-D-24-01599 Abstract ( 161 )   PDF (1658KB) ( 404 )   Save Recent studies have found that the suppression of phosphatase and tensin homolog is one of the most effective single-gene approaches for promoting optic nerve regeneration. This effect is primarily mediated through the activation of the protein kinase B/phosphoinositide 3-kinase/mammalian target of rapamycin signaling pathway. The purpose of this article is to elucidate how the downregulation of phosphatase and tensin homolog is involved in each key phase of optic nerve regeneration and to summarize the potential targets for therapeutic interventions in this process. Optic nerve regeneration progresses through five phases: stress response, growth navigation, nerve regeneration, synaptic reconstruction, and remyelination. During the stress response phase, the suppression of phosphatase and tensin homolog enhances the survival of retinal ganglion cells and promotes the proliferation of microglia. In the nerve regeneration phase, reduced levels of phosphatase and tensin homolog facilitate mitochondrial transport, while inhibition of the phosphatase and tensin homolog-L isoform specifically promotes mitophagy. During the synaptic reconstruction phase, the deletion of phosphatase and tensin homolog modulates the synthesis of axon extension-related proteins and stabilizes microglial microtubules, thereby accelerating the clearance of damaged synapses and the formation of new ones. During the remyelination phase, the knockout of phosphatase and tensin homolog promotes the proliferation of oligodendrocyte progenitor cells and the differentiation of oligodendrocytes, relieving myelination obstruction. This paper also discusses current strategies and translational challenges for neuron-specific inhibition of phosphatase and tensin homolog, including off-target effects, delivery precision, and long-term safety. By integrating molecular insights with emerging bioengineering approaches, this paper provides a framework for developing targeted therapies for optic nerve regeneration and broader applications in the field of central nervous system regeneration. Related Articles | Metrics

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Brain organoids and genome editing: A new era in understanding human brain development and disorders Min Zhou, Yuanqing Cao, Ke Yue, Wenyu Wu, Yutong Xie, Daiyu Hu, Jingjing Zhao, Fang Xu, Jianrong Guo, Zhenzhou Li, Huan Wang, Zhengliang Gao 2026, 21 (7):  2761-2771.  doi: 10.4103/NRR.NRR-D-24-01546 Abstract ( 160 )   PDF (2224KB) ( 1192 )   Save Brain organoids are artificial neural tissues derived in vitro, containing a variety of cell types, as well as structural and/or functional brain regions. They can partially mimic brain physiological activities and diseased processes. Owing to their operability and sample accessibility, brain organoids serve as a bridge between in vitro monolayer cell culture models and in vivo animal models. An increasing number of induction protocols for brain organoids have been developed over the preceding decade. A key future research direction will focus on ensuring the complexity and quality of brain organoids. The integration of powerful technologies, such as the CRISPR/Cas9 genome editing and lineage tracing systems, shall precipitate practical and broad applications of brain organoids. In this review, we discuss the generation and application of brain organoids, as well as their integration with genome editing technologies, in the study of neural development, disease modeling, and mechanistic investigations. The innovative combination of these two technologies may offer a fresh perspective for exploring the fundamental aspects of the human nervous system and related diseases. Related Articles | Metrics

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MicroRNAs in the pathogenesis of neurodegenerative disorders: Potential as therapeutic targets Aditi Singh , Manivannan Subramanian , Amit Singh 2026, 21 (7):  2772-2778.  doi: 10.4103/NRR.NRR-D-25-00402 Abstract ( 126 )   PDF (1414KB) ( 49 )   Save Neurodegenerative diseases (neurodegenerative disorders) are marked by the progressive degeneration of the structure and function of the central nervous system. They may result in the deterioration of cognitive, motor, and functional abilities. Diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis represent some of the most prominent examples of neurodegenerative disorders. Despite scientific advancement in understanding disease pathology and prognosis, the therapeutic strategies available for management remain limited. In recent years, microRNAs, small non-coding RNA molecules, have emerged as key players in the pathogenesis of neurodegenerative disorders. Therefore, understanding how these microRNAs affect disease pathology and pathway signaling is essential, and may open microRNAs as new avenues for potential therapeutic intervention. This review explores the role of microRNAs in various neurodegenerative diseases, discuss how microRNAs affect signaling pathways, and examine the potential of microRNAs as therapeutic targets. Related Articles | Metrics

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Lipid metabolism, microglia, and stroke Lei Chen, Minmin Zhang, Wei Wei, Qiang Li, Lijun Wang, Ming Zhao, He Li, Hongye Xu, Pengfei Yang, Ping Zhang 2026, 21 (7):  2779-2795.  doi: 10.4103/NRR.NRR-D-24-01523 Abstract ( 285 )   PDF (1968KB) ( 136 )   Save Microglia, lipids, and their interaction are found to play important roles in post-stroke immunity. Microglia are sensitive to detect environment change in injured brain. Activated microglia undergo phenotypical remodeling and trigger complex signal cascades to regulate immune responses after stroke. Lipids including peripheral lipid metabolism and lipid droplet biogenesis are involved in the control of microglia functions, such as activation, phagocytosis, proliferation, and pro-inflammation. In this review, we explore new scope of microglia and lipids in immune regulation of stroke. Implication of peripheral lipid metabolism after stroke is mentioned and advances in microglia-lipid interaction are discussed. We give a special focus on how diet and gut microbiome influence neuroinflammation system via gut–brain axis, and how these processes associate with the risk and outcome of stroke. Moreover, we reviewed the therapeutic targets related to lipid metabolism and microglial modulation after stroke. These can provide a prospective strategy for more efficient and safer treatment for ischemic and hemorrhagic stroke. Related Articles | Metrics

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The roles of microglia and astrocytes in inflammasomes and neurological disorders Yuze Xia, Yimin Huang, Yuan Liu, Xincheng Zhang, Huayu Kang, Yanchao Liu, Chenxuan Yu, Chao Gan, Huaqiu Zhang 2026, 21 (7):  2796-2805.  doi: 10.4103/NRR.NRR-D-24-01574 Abstract ( 102 )   PDF (3482KB) ( 25 )   Save Inflammasomes, a category of protein complexes, recognize exogenous pathogens and endogenous tissue damage. In response, they induce inflammatory responses and pyroptosis, and are involved in both innate immunity and the regulation of adaptive immunity, with significant effects in disease and health. Neuroinflammation is closely related to neurological disorders. Nervous system homeostasis is primarily regulated by glial cells, with microglia and astrocytes playing a dual role in both neuroprotection and neurotoxicity. Recent studies highlight the importance of microglia and astrocytes within the central nervous system in mediating neuroinflammation associated with neuropsychiatric diseases. In particular, the role of inflammasomes in glial cells and neuroinflammation has garnered growing attention. This review classifies inflammasomes and their activation mechanisms as well as explores their involvement in the activation of microglia and astrocytes in various neurological diseases, aiming to contribute a deeper understanding of the pathogenesis of neurodegenerative disease and brain injury and identification of novel therapeutic targets. Related Articles | Metrics

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Palmitic acid–induced autolysosomal dysfunction and lipotoxicity in neuroinflammation and neurodegeneration Eka Norfaishanty Saipuljumri, Jialiu Zeng, Chih Hung Lo 2026, 21 (7):  2806-2811.  doi: 10.4103/NRR.NRR-D-25-00432 Abstract ( 177 )   PDF (2543KB) ( 89 )   Save Neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases are increasingly associated with metabolic dysfunction, including obesity, type 2 diabetes, and metabolic dysfunction–associated steatotic liver disease. Central to this connection is the dysregulation of lipid metabolism, which extends beyond peripheral tissues to the brain, defective autolysosomal function, oxidative stress, inflammation, and insulin resistance. Lipids, which constitute over half of dry weight of the brain, play critical roles in energy provision, structural integrity, and synaptic function. Dysregulation of lipid metabolism contributes to neuroinflammation, impaired neuronal function, and disrupted blood–brain barrier integrity. Palmitic acid, a saturated fatty acid abundant in high-fat diets, serves as a key model for studying lipid-induced toxicity (lipotoxicity) in the brain. Palmitic acid disrupts autophagy and lysosomal function, mitochondrial function, triggering oxidative stress, contributing to neuroinflammation and neurodegeneration. These effects are particularly pronounced in neurons, which are highly susceptible to lipid-induced toxicity due to their high metabolic demands. Glial cells, including astrocytes, microglia, and oligodendrocytes, also exhibit distinct vulnerabilities and adaptive responses to lipid metabolism dysregulation, further contributing to neuroinflammation and demyelination. Therapeutic strategies, such as supplementation with polyunsaturated fatty acids, AMP-activated protein kinase activation, and lysosome-targeted interventions, show promise in mitigating palmitic acid–induced lipotoxicity and restoring cellular homeostasis. This review comprehensively examines palmitic acid–induced lipotoxicity and its impact on autolysosomal dysfunction across various central nervous system cell types, including neurons, astrocytes, microglia, and oligodendrocytes. Additionally, it highlights therapeutic approaches to restore autolysosomal function under lipotoxic conditions. Advances in multi-omics technologies and a deeper understanding of intercellular crosstalk offer new avenues for developing targeted therapies to restore autolysosomal function, and attenuate neuroinflammation and neurodegeneration. Related Articles | Metrics

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Interplay between brain-specific microRNAs and Alzheimer’s disease Nathan Tinu, Bhupender Sharma, Daniela Rodarte, Rajkumar Lakshmanaswamy, Subodh Kumar 2026, 21 (7):  2812-2823.  doi: 10.4103/NRR.NRR-D-25-00190 Abstract ( 167 )   PDF (1261KB) ( 84 )   Save Alzheimer’s disease is a progressive neurodegenerative disease characterized by memory decline and the accumulation of abnormal protein aggregates in the brain. While the precise cause of Alzheimer’s disease remains under investigation, recent research suggests that dysregulation of brainspecific microRNAs (miRs) plays a significant role in Alzheimer’s disease pathogenesis. Brain-specific miRs are predominantly expressed within the central nervous system and are crucial for neuronal development, and function, potentially in brain disorders. This review identifies some key brainspecific miRs in Alzheimer’s disease, including miR-9, miR-26b, miR-34a, miR-107, miR-124, miR125b, miR-128, miR-132, miR-146a, miR-155, miR-219, miR-501-3p, and miR-502-3p. The review also shed light on the brain-specific location of these miRs, their dysregulation in Alzheimer’s disease, and how they are involved in disease progression. Apparently, these brain-specific miRs modulate specific genes and are therefore crucial for various cellular processes, including autophagy, cell cycle, tau phosphorylation, amyloid-beta production, and neuroinflammation. Moreover, these miRs are potent disease-modifying factors and their expression levels could serve as potential biomarkers for diagnosing or monitoring Alzheimer’s disease progression. Related Articles | Metrics

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Emerging role of copper in the pathophysiology of spinal cord injury Wenjing Ni, Peiling Qiu, Yang Huang, Sheng Wang, Xiaolei Zhang, Yifei Zhou, Di Zhang 2026, 21 (7):  2824-2842.  doi: 10.4103/NRR.NRR-D-24-01449 Abstract ( 152 )   PDF (9171KB) ( 36 )   Save Copper is a trace element that plays an important role in neuronal development, maturation, and function. It also acts as a cofactor for various copper-binding proteins or serves as an active component of their structure. Acquired copper deficiency has been associated with numerous neurological diseases. Recent research has demonstrated that serum copper concentrations are elevated following spinal cord injury, similar to the elevated copper levels observed after ischemic insult in a rat model of myocardial infarction. This suggests that spinal cord damage may impair the effective utilization of copper due to local ischemia following spinal cord injury. Studies have shown that copper supplementation may form part of a therapeutic strategy for patients with spinal cord injury. It has been reported to promote T-cell differentiation and proliferation, reduce malondialdehyde levels, decrease myeloperoxidase activity and apoptotic cell numbers, and enhance superoxide dismutase activity and glutathione levels. Additionally, copper supplementation may stimulate the transcriptional activity of hypoxia-inducible factor and restore angiogenic capacity, thereby increasing capillary density. Furthermore, researchers have found that dihydrolipoamide dehydrogenase, an enzyme involved in inducing cuproptosis, can influence the immune microenvironment of spinal cord injury by promoting copper toxicity. This leads to increased peripheral M2 macrophage polarization and systemic immunosuppression. This led us to hypothesize that copper may influence three major pathological pathways after spinal cord injury, inflammation, oxidative stress, and cell death, which are critical targets for therapeutic intervention. On the one hand, copper deficiency can cause spinal cord tissue damage; on the other hand, elevated serum copper may induce copper toxicity, contributing to cell death. Therefore, in this review, we investigate the possible link between spinal cord injury and copper in the perspective of inflammation, oxidative stress, and cell death. Additionally, we review published studies on copper metabolism and explore potential therapeutic strategies by considering various sources and mechanisms of copper delivery. Related Articles | Metrics

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Application strategies of autologous and decellularized nerve grafts: Structural and functional recovery Xiaoqi Yang, Nianci Huo, Hui Zhou, Senrui Li, Mengyuan Fang, Nan Zhou 2026, 21 (7):  2843-2862.  doi: 10.4103/NRR.NRR-D-25-00607 Abstract ( 196 )   PDF (5808KB) ( 154 )   Save Autologous nerve transplantation is currently recognized as the gold standard for treating severe peripheral nerve injuries in clinical practice. However, challenges such as a limited supply of donors, complications in the donor area, and the formation of neuromas necessitate the optimization of existing transplantation strategies. Additionally, the development of new and promising repair methods is a critical issue in the field of peripheral nerve research. The purpose of this article is to compare the advantages and disadvantages of autologous, allogeneic, decellularized nerve grafts, and cell-composite graft, as well as to summarize the differences in their prognostic factors and associated adverse events. The length, diameter, polarity, and sensory or motor origin of autografts all influence axonal regeneration. While pre-denaturation treatment can accelerate early regeneration, long-term functional outcomes of autografts do not show significant differences compared with fresh autologous grafts. For decellularized nerve grafts, defect length is identified as an independent risk factor, and the internal microenvironment (delayed angiogenesis, Schwann cell senescence, and reduced T-cell infiltration) is considered a key factor limiting long-segment regeneration. Additionally, the decellularization process (whether chemical, physical, or supercritical CO2) affects the integrity of the extracellular matrix and the presence of immune residuals, which directly impacts axonal guidance and host integration. Common adverse events following autograft transplantation include donor site numbness, neuromas, and scarring. In contrast, adverse events associated with decellularized nerve graft transplantation may present as inflammatory reactions, excessive scar proliferation, and misalignment or reconnection of regenerating axons, which can lead to sensory–motor cross-innervation. To mitigate these issues, combining decellularized nerve grafts with autologous Schwann cells, mesenchymal stem cells, or induced pluripotent stem cell– derived cells may help bridge the gap with autografts. However, the fact that structural recovery does not necessarily lead to functional recovery needs further clarification. Future research should establish large animal models to replicate the limits of human regenerative capacity, use gene editing to enhance the phenotype and microenvironment of transplanted cells, and develop a mild combined decellularization process that maximizes the preservation of natural nerve grafts. Through multidimensional optimization, decellularized nerve grafts have the potential to ultimately replace autograft transplantation, enabling precise repair of individualized, long-segment, and complex nerve defects. Related Articles | Metrics

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MicroRNA and Alzheimer’s disease: Diagnostic biomarkers and potential therapeutic targets Yiwen Huang, Yimin Chen, Zhengyang He, Wenfeng Lu, Hejin Lai, Yu Wang, Jie Wang 2026, 21 (7):  2863-2881.  doi: 10.4103/NRR.NRR-D-25-00002 Abstract ( 156 )   PDF (7861KB) ( 39 )   Save MicroRNAs (miRNAs), small non-coding RNAs ranging from 19 to 25 nucleotides in length, are key regulators of gene expression that function primarily by inhibiting the translation of target mRNAs. Recent studies have suggested that miRNAs play important roles in regulating key aspects in the pathology of Alzheimer’s disease, including the modulation and accumulation of amyloid-beta and tau proteins. Moreover, miRNAs have been implicated in the regulation of neuroinflammation through various inflammatory pathways, notably the nuclear factor kappa B signaling cascade. Additional emerging evidence has shown that miRNAs regulate synaptic growth and maturation, and they perform promising roles in regulating neuronal death and development. miRNAs also offer a novel avenue for direct reprogramming of neurons, representing a promising strategy for Alzheimer’s disease treatment. The regulation of miRNA biogenesis and the post-transcriptional modifications of miRNAs are critical factors in Alzheimer’s disease pathology, influencing miRNA activity and disease progression. In this review, we comprehensively explore the role of different miRNAs in regulating various pathological processes associated with Alzheimer’s disease, focusing primarily on four representative miRNAs: miR-9, miR-29, miR-126, and miR-146a for further exploration. We also discuss the influence of miRNA biogenesis on Alzheimer’s disease, emphasizing how dysregulation of miRNA processing may contribute to the disease. Additionally, we highlight the potential of miRNAs as both diagnostic biomarkers and therapeutic targets in Alzheimer’s disease, along with promising vector delivery strategies aimed at improving clinical outcomes. Finally, we discuss the challenges and limitations associated with the use of miRNAs in the diagnosis and treatment of Alzheimer’s disease. By reviewing the current clinical applications of miRNAs as biomarkers and therapeutic agents, we aim to provide insights that will inform future research and development in this promising field. Related Articles | Metrics

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Six promising drug repurposing candidates for Alzheimer’s disease and their sex-specific mechanisms and efficacy Maria E. Figueiredo-Pereira, Peter A. Serrano, Patricia Rockwell 2026, 21 (7):  2882-2888.  doi: 10.4103/NRR.NRR-D-25-00256 Abstract ( 129 )   PDF (2095KB) ( 77 )   Save Alzheimer’s disease is a neurodegenerative disorder that leads to progressive memory loss, cognitive decline, and behavioral changes. Despite ongoing research, its exact causes and effective treatments remain elusive. Traditional approaches have focused on symptom management, but breakthroughs in bioinformatics and high-throughput drug screening are offering new pathways to potential therapies. This review highlights our recent efforts to identify novel drug candidates for Alzheimer’s disease by leveraging computational methods and large-scale biological datasets. Our work introduces two key innovations in Alzheimer’s disease research: addressing sex-specific differences and leveraging drug repurposing for accelerated treatment discovery. By combining sex-stratified preclinical data with machine learning and in vivo validation, we improve translational relevance and support precision medicine. Using the TgF344-AD rat model, which mimics human Alzheimer’s disease spatial memory deficits and pathology, we explored the efficacy of various US Food and Drug Administration– approved and investigational drugs. These included ibudilast, timapiprant, RG2833, diazoxide/ dibenzoylmethane (combined), and BT-11, which targeted key Alzheimer’s disease–related molecular pathways such as amyloid-beta plaques, Tau tangles, and neuroinflammation. These drugs, at various stages of development, offer hope for not only managing symptoms but also addressing the underlying mechanisms of Alzheimer’s disease. This review underscores the need for a multifaceted approach to Alzheimer’s disease treatment, combining symptom relief with disease modification. Related Articles | Metrics

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Deep brain stimulation of the nucleus basalis of Meynert in neurodegenerative diseases with cognitive impairment: An update on evidence and mechanisms Xuyang Liu , Kai Shu , Liwu Jiao , Yumei Geng , Mengying Wang , Huicong Kang 2026, 21 (7):  2889-2898.  doi: 10.4103/NRR.NRR-D-24-00838 Abstract ( 163 )   PDF (10456KB) ( 12 )   Save Current pharmacotherapy for neurodegenerative diseases is limited to providing symptomatic relief, instead of slowing or reversing disease progression. As a form of neuromodulation surgery, deep brain stimulation delivers electrical pulses through implanted electrodes in targeted brain regions and has been used to alleviate symptoms in neurodegenerative diseases. Depending on the precise targeting of neural modulation, deep brain stimulation is being explored for its potential to manage symptoms and improve overall quality of life in neurodegenerative diseases associated with cognitive impairment, such as Alzheimer’s disease and dementia in Parkinson’s disease. The nucleus basalis of Meynert, a critical component of the cerebral cholinergic system and the Papez circuit, is considered as a promising target for treating cognitive dysfunction in neurodegenerative diseases due to its essential role in regulating cognition, memory, and attention. However, the comprehensive mechanisms by which deep brain stimulation of nucleus basalis of Meynert affects neurodegenerative diseases with cognitive impairment remain largely uncharacterized. Nonetheless, various hypotheses and evidence from animal and clinical studies suggest mechanisms such as the modeulation of the cholinergic system, increased glucose metabolism and regional cerebral blood flow, neuroprotective effects, and the modulation of neural networks. In this review, we update the advances in research regarding the therapeutic effects and potential mechanisms of deep brain stimulation of nucleus basalis of Meynert on cognitive impairment in neurodegenerative diseases. Additionally, we examine the anatomy, connectivity, and physiological functions of the nucleus basalis of Meynert. Deep brain stimulation of nucleus basalis of Meynert may improve cognitive impairment in neurodegenerative diseases through multiple mechanisms; however, further larger-scale, multi-center clinical trials conducted at earlier disease stages are necessary to fully confirm its efficacy and safety. Related Articles | Metrics

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Bridging autophagy and endolysosomal dysfunction: Role of bridging integrator 1 in Alzheimer’s disease Julia Duckhorn, Doo Kyung Kim, Yu-Wen Alvin Huang 2026, 21 (7):  2899-2911.  doi: 10.4103/NRR.NRR-D-25-00243 Abstract ( 129 )   PDF (1714KB) ( 1144 )   Save Alzheimer’s disease is a devastating neurodegenerative disorder affecting millions worldwide, with current treatments offering only limited benefits. Central to emerging research is the role of autophagy and endolysosomal pathways, which are essential for clearing misfolded proteins and damaged organelles. Bridging integrator 1 (BIN1), traditionally recognized for its role in membrane remodeling and endocytosis, has recently emerged as a top genetic risk factor for Alzheimer’s disease, linking cellular clearance mechanisms to the development of toxic amyloid-beta plaques and tau tangles. In this review, we provide an accessible overview of how disruptions in autophagy and endolysosomal trafficking contribute to the neurodegeneration process in Alzheimer’s disease, positioning BIN1 as a central mediator within this complex network. Recent advances have shown that alterations in BIN1 expression and isoform distribution are associated with increased tau pathology and changes in amyloid-beta processing. Moreover, BIN1 appears to also influence synaptic transmission, neuroinflammation, and overall cellular homeostasis. The integration of recent findings not only deepens our understanding of Alzheimer’s disease pathology but also opens new avenues for the development of targeted treatments. This timely perspective underscores the potential of modulating BIN1 activity to enhance cellular clearance mechanisms and offers hope for more effective interventions for Alzheimer’s disease. Related Articles | Metrics

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Sonic Hedgehog signaling in oligodendrogenesis, myelination, demyelinating diseases, and remyelination Miguel Marchena-Fernández, Cristina Sánchez-Camacho , Emma Muñoz-Sáez, Alba Macías-Castellano, Fernando de Castro Soubriet 2026, 21 (7):  2912-2913.  doi: 10.4103/NRR.NRR-D-25-00005 Abstract ( 120 )   PDF (1024KB) ( 80 )   Save The Hedgehog (HH) family includes Indian (IHH), Desert (DHH), and Sonic Hedgehog (SHH). Proteins of the HH family are distinguished by their function as morphogens, i.e., molecules that regulate the pattern of tissue development in accordance with concentration gradient. Data accumulated over the years clearly demonstrate that HH signaling is essential in myelination, particularly in the life cycle of the oligodendrocyte lineage. DHH is a key factor for Schwann cell function in the myelination of the peripheral nervous system and IHH is directly involved in the specification of oligodendrocyte precursor cells (OPCs) at least in the zebrafish. The most studied family member in central nervous system (CNS) myelination is SHH. SHH signaling has been identified as a crucial component in oligodendrocyte differentiation and remyelination (Russo et al., 2024). SHH is synthetized as a 46 kDa precursor protein which undergoes an autoproteolytic cleavage producing the excision of 19 kDa amino-terminal region (HH-N) and SHH carboxy-terminal polypeptide. The HH-N domain binds cholesterol and palmitic acid producing a functional signaling molecule. Related Articles | Metrics

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Astrocytic NLRP6 inflammasome: From protective sentinels to drivers of alcohol-induced neuroinflammation Seema Singh, Shilpa Buch, Palsamy Periyasamy 2026, 21 (7):  2914-2915.  doi: 10.4103/NRR.NRR-D-24-01620 Abstract ( 122 )   PDF (813KB) ( 33 )   Save The innate immune system of the central nervous system (CNS), long viewed as primarily microgliadriven, is now increasingly recognized to include astrocytes as active participants in neuroimmune signaling. Chronic alcohol exposure triggers oxidative stress, glial activation, and sustained inflammation, ultimately contributing to cognitive decline and neuronal injury. While microglial inflammasomes, particularly nucleotide-binding domain, leucinerich–containing family, pyrin domain–containing-3 (NLRP3), have garnered attention in alcohol-related neuroinflammation, the recent study by Singh et al. (2025) extends this paradigm by identifying a miR-339-regulated NLRP6 inflammasome response in human fetal astrocytes exposed to ethanol. Their findings shed light on a potential astrocytespecific inflammatory mechanism, but also raise key questions about its translational applicability (Figure 1). Specifically, the use of proliferating fetal astrocytes as a model system may better reflect mechanisms relevant to fetal alcohol spectrum disorders than adult alcohol use disorder (AUD). Furthermore, the focus on a single inflammasome axis overlooks the complex interplay among multiple innate immune sensors and their divergent roles across CNS cell types and species. In this Perspective, we critically examine the implications of the miR-339/NLRP6 axis in the broader landscape of astrocytic inflammasome research, discuss the limitations of the current model system, and highlight future directions for establishing NLRP6 as a viable therapeutic target for alcohol-induced neuroinflammation. Related Articles | Metrics

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Rethinking microglia from a circadian perspective in neuroimmunology: New insights Daniele Mattei 2026, 21 (7):  2916-2917.  doi: 10.4103/NRR.NRR-D-25-00157 Abstract ( 128 )   PDF (933KB) ( 35 )   Save Microglia cells are the resident innate immune cells of the central nervous system (CNS) (Paolicelli et al., 2022). They play a pivotal role in CNS development and in maintaining homeostasis during adulthood. Microglia are being extensively studied for their involvement in CNS disorders, ranging from autoimmune diseases such as multiple sclerosis to neurodegenerative and psychiatric conditions, as well as stroke and brain tumors (Paolicelli et al., 2022). To harness microglia in therapeutic development, we need to deepen our understanding of their intricate biology. Our knowledge of microglia biology has evolved significantly with technological advancements, leading to a progressive “rethinking” of microglia cells within the field. Initially viewed as static cells, we now understand microglia to be highly motile and constantly surveillant. Once thought to be a homogeneous population of CNS macrophages, microglia are now recognized to occupy a range of cellular states (Paolicelli et al., 2022). Importantly, emerging evidence highlights circadian and diurnal rhythms as key contributors to microglial immune reactivity, morphology, and functions such as phagocytosis (Gu et al., 2023; GuzmánRuiz et al., 2023; Jiao et al., 2024). Circadian rhythms refer to physiological oscillations dictated by the endogenous biological clock, while diurnal rhythms refer to physiological variations set by external light cues that function as Zeitgeber time (ZT, German word for time-giver), such as the lightdark cycle (Guzmán-Ruiz et al., 2023). Currently, most microglial studies do not account for these oscillations, which can significantly impact study design and data interpretation. This perspective article aims to discuss why implementing a circadian framework in preclinical research is essential for advancing our understanding of microglia cells in both physiology and disease. Related Articles | Metrics

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Gamma entrainment as a functional target in deep brain stimulation Bandy Chen 2026, 21 (7):  2918-2919.  doi: 10.4103/NRR.NRR-D-25-00510 Abstract ( 144 )   PDF (605KB) ( 23 )   Save Deep brain stimulation (DBS) is a neuromodulation tool that involves the delivery of electrical impulses to specific brain regions through implanted electrodes. The principle behind DBS is to modulate dysfunctional neural circuits without the need for permanent structural alterations to the brain. Initially developed as a treatment for movement disorders such as Parkinson’s disease (PD), DBS has expanded to encompass various neurological and psychiatric disorders. Until recently, DBS uses high-frequency electrical pulses to disrupt abnormal patterns of brain activity. Recent advances in neuroscience are shifting toward precision-based rhythm restoration with the goal of reinstating normal oscillatory patterns. Entrainment of brain activity within the gamma range (30–100 Hz), particularly around 40 Hz, has demonstrated potential in improving neurological disorders such as Alzheimer’s disease (AD) and PD (Deng et al., 2024). This represents a shift in the goal of DBS from silencing neural circuits to restoring physiological brain rhythms. Related Articles | Metrics

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Valosin-containing protein, neural proteopathies, and implications for neural regeneration Jae-Geun Lee, Eun-Ji Lee, Hoon Ryu, Jeong-Soo Lee 2026, 21 (7):  2920-2921.  doi: 10.4103/NRR.NRR-D-25-00442 Abstract ( 114 )   PDF (811KB) ( 31 )   Save Proteostasis, also known as protein homeostasis, is a tightly regulated cellular quality control process that ensures the balance of protein synthesis, folding, posttranslational modifications, and degradation. Maintaining proteostasis is vital for cellular function, organismal health, and longevity. The disruption of proteostasis can lead to a range of detrimental effects, including accelerated aging, compromised cellular function, and even cell death, manifesting in numerous human diseases (Hipp et al., 2019). Neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases (AD, PD, HD, respectively), are often characterized by the accumulation of misfolded proteins that aggregate into granules or inclusions. These aggregates form when proteins lose their proper conformation and fail to be refolded or degraded efficiently due to the failure of proteostasis. The persistence of these pathological protein aggregates can interfere with cellular processes, disrupt organelle function, and ultimately contribute to disease progression (Hipp et al., 2019). Related Articles | Metrics

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Mitochondria-derived vesicles in neurodegeneration Emanuele Marzetti, Riccardo Calvani, Hélio José Coelho-Júnior, Anna Picca 2026, 21 (7):  2922-2923.  doi: 10.4103/NRR.NRR-D-25-00305 Abstract ( 131 )   PDF (1735KB) ( 32 )   Save Mitophagy is a well-characterized and redundant recycling system for damaged mitochondria and a marker of organelle quality (Picca et al., 2023). Yet, the assessment of mitophagy in vivo remains a challenge. The characterization of the endosomallysosomal pathways supporting the endocytic trafficking has provided invaluable information also into mitophagy signaling. The endocytic pathway has been implicated in preserving mitochondrial quality via generation of mitochondria-derived vesicles (MDVs) and, as such, has been related to mitophagy tasks (Ferrucci et al., 2024). Altered mitophagy and MDV signaling accompany brain aging and neurodegenerative conditions (Ferrucci et al., 2024). However, how MDVs can be best characterized to be exploited as hallmarks of health and disease is debated. MDVs may be a trait d’union between dysfunctional mitophagy and decline of cell homeostasis through shuttling and/or being themselves mitochondriaderived damage-associated molecular patterns. These latter by instigating chronic low-grade inflammation may support neuroinflammation and neurodegeneration (Ferrucci et al., 2024). Alternatively, MDVs may rescue mitochondrial bioenergetics of neighbouring cells and favour neuronal health by transferring functional organelles. However, what defines one or the other role of MDVs and whether the outcome is mediated by vesicle subpopulations released under different metabolic triggers remain to be defined. Herein, we discuss MDVs as surrogate and more accessible measures of mitophagy. We also highlight the importance of addressing challenges in MDVs isolation and characterization to appreciate their signaling roles in neurodegeneration. Related Articles | Metrics

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Pathogenic landscape shaped by cerebral amyloid oligomers Yujing Huang , Mengze Xu , Zhen Yuan , Pu Chun Ke 2026, 21 (7):  2924-2925.  doi: 10.4103/NRR.NRR-D-25-00557 Abstract ( 106 )   PDF (993KB) ( 48 )   Save Amyloid oligomers, a brief history: Amyloid d i s e a s e s e n c o m p a s s a r a n g e o f h u m a n neurological, systemic, and metabolic disorders, characterized by the common feature of amyloid fibril and plaque deposition, either intracellularly or extracellularly. Among them, Alzheimer’s disease (AD)—manifested by memory loss and cognitive decline—and Parkinson’s disease (PD)— underlined by impaired dopamine release and motor dysfunction—are the two most prevalent forms of neurodegenerative conditions that have rapidly become global epidemics. Type 2 diabetes, conversely, is a prevalent metabolic disorder underpinned by pancreatic beta cell loss, elicited primarily by the aggregation and toxicity of human islet amyloid peptide. Related Articles | Metrics

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Rethinking dementia in the oldest old: Lessons to learn for the diagnosis and treatment of Alzheimer’s disease Chiara Giuseppina Bonomi, Caterina Motta, Martina Gaia Di Donna, Martina Poli, Giacomo Koch, Alessandro Martorana 2026, 21 (7):  2926-2927.  doi: 10.4103/NRR.NRR-D-25-00312 Abstract ( 111 )   PDF (623KB) ( 28 )   Save Dementia and Alzheimer’s disease (AD) are both age-related conditions that predominantly affect older adults. According to prevalence studies, the burden of these diseases on society is expected to increase in the coming years, particularly in relation to rising longevity and life expectancy. Advances in therapeutic and preventive strategies are needed to help reduce their global burden, which remains among the most significant health challenges in aging populations (Brookmeyer et al., 2007). Related Articles | Metrics

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Neural networks and econometric models: Advancing brain connectivity for Alzheimer’s drug development Lorenzo Pini , Paolo Pigato, Gloria Menegaz, Ilaria Boscolo Galazzo 2026, 21 (7):  2928-2929.  doi: 10.4103/NRR.NRR-D-25-00317 Abstract ( 99 )   PDF (2168KB) ( 55 )   Save Advances in Alzheimer’s disease (AD) research have deepened our understanding, yet the mechanisms driving its progression remain unclear. Although a range of in vivo biomarkers is now available (e.g., measurements of amyloidbeta (Aβ) and tau accumulation – the molecular hallmarks of AD – structural magnetic resonance imaging (MRI), assessments of brain metabolism, and, more recently, blood-based markers), a definitive diagnosis of AD continues to be challenging. For example, Frisoni et al. (2022) proposed a shift from a deterministic, amyloidcentered approach to a probabilistic framework that integrates genetic and environmental factors. Similarly, Dubois et al. (2024) cautioned against diagnosing AD based solely on molecular markers in cognitively normal individuals, advocating instead for the designation of “at risk” individuals. These perspectives reflect an evolving understanding of AD that is continuously reshaping both clinical and pharmacological approaches. Moreover, the recent approval of two diseasemodifying agents (Lecanemab and Donanemab) that target misfolded Aβ proteins has underscored significant limitations, particularly their moderate impact on clinical and cognitive outcomes. The discrepancy between the improvements in AD biomarkers with anti-Aβ drugs and their limited clinical benefits underscores the need for a new paradigm. In this context, assessing Aβ levels can be compared to measuring blood pressure: just as high blood pressure does not inevitably lead to cardiovascular disease, and some individuals with the disease may not have elevated blood pressure, the multifactorial nature of AD suggests that Aβ accumulation alone does not define the disease. Related Articles | Metrics

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Transcription factor NR2F1 is involved in Parkinson’s disease Annemarie de Vries, Silvia Bolognin 2026, 21 (7):  2930-2931.  doi: 10.4103/NRR.NRR-D-25-00290 Abstract ( 122 )   PDF (751KB) ( 55 )   Save Nuclear receptor subfamily 2 group F member 1 (NR2F1, also called COUP-TF1) is a transcription factor and part of the steroid/thyroid hormone receptor superfamily (Gay et al., 2002). NR2F1 is an orphan receptor that dimerizes to bind DNA and acts as a repressor as well as an activator of the target genes (Gay et al., 2002; Bertacchi et al., 2019; Bonzano et al., 2023). It was found recently to regulate the transcription of mitochondrial genes and to affect the morphology and mass of mitochondria (Bonzano et al., 2023). NR2F1 is mainly known for its pleiotropic role in neurodevelopment, but it has recently been connected to neurodegeneration in the context of Parkinson’s disease (PD) (Walter et al., 2021). This perspective summarizes the known functions of NR2F1 and offers a new perspective on its potential role in neurodegeneration. Related Articles | Metrics

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Antigen presentation at the brain barriers in multiple sclerosis Joshua Brands, Jeroen Bogie, Bieke Broux 2026, 21 (7):  2932-2933.  doi: 10.4103/NRR.NRR-D-25-00206 Abstract ( 127 )   PDF (2722KB) ( 37 )   Save Loss of immune tolerance to central nervous system (CNS) antigens lies at the heart of multiple sclerosis (MS), the most common chronic autoimmune disease of the CNS. MS affects nearly 2 million people worldwide and is characterized by focal areas of demyelination, inflammation, axonal injury, and neurodegeneration (Bronge et al., 2022; Magliozzi et al., 2023). The condition leads to symptoms such as numbness, muscle weakness, fatigue, visual impairment, and cognitive decline (Magliozzi et al., 2023). Although autoreactive T cells are considered to be primed in peripheral lymphoid tissues initially, it is the local reactivation of these T cells upon encountering CNS antigens that critically drives the inflammatory response within the CNS (Koch et al., 2022). It has become increasingly apparent that brain barriers, such as the blood–brain barrier (BBB), the blood– cerebrospinal fluid barrier (BCSFB), and the meninges, are central to modulating the immune response and driving MS pathology, potentially by facilitating antigen presentation and thus T cell reactivation (Ampie and McGavern, 2022; Magliozzi et al., 2023; Zierfuss et al., 2024). In this perspective, we examine current evidence on how antigen presentation occurs at major brain barrier sites and their contribution to triggering MS onset and progression. Related Articles | Metrics

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Proteostasis decline and endoplasmic reticulum stress in aging: Implications for cellular senescence and senescence-associated secretory phenotype regulation Philippe Pihán, Lisa M. Ellerby, Claudio Hetz 2026, 21 (7):  2934-2935.  doi: 10.4103/NRR.NRR-D-25-00161 Abstract ( 172 )   PDF (599KB) ( 51 )   Save Aging is a universal biological process characterized by the progressive decline in cellular and tissue function, representing the main risk factor for the development of most chronic human diseases. At the cellular level, one hallmark of aging is the accumulation of senescent cells—non-dividing yet metabolically active cells that adopt a unique phenotype, including the senescence-associated secretory phenotype (SASP) (Wang et al., 2024). The SASP encompasses a complex secretory program of bioactive molecules, including proinflammatory cytokines such as interleukin-6, interleukin-1 beta, and tumor necrosis factoralpha; chemokines such as CXC motif chemokine ligand 8/interleukin-8 and C-C motif chemokine ligand 2; growth factors such as vascular endothelial growth factor and hepatocyte growth factor; and matrix-remodeling enzymes such as matrix metalloproteinases. These factors influence the surrounding microenvironment by promoting inflammation, tissue remodeling, and paracrineinduced senescence. While the SASP may play a beneficial role in acute stress responses such as wound healing and tumor suppression, its chronic persistence contributes to systemic inflammation, stem cell exhaustion, and age-associated pathologies (Wang et al., 2024). Related Articles | Metrics

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Cholinergic pathways in neural stem cell regulation and glioblastoma progression: Shared origins and mechanisms Moawiah M. Naffaa 2026, 21 (7):  2936-2937.  doi: 10.4103/NRR.NRR-D-25-00288 Abstract ( 124 )   PDF (1598KB) ( 51 )   Save Neural stem cells (NSCs) and glioblastoma stem cells (GSCs) share a complex regulatory landscape in which cholinergic signaling plays a pivotal role in both neural development and tumor progression. While acetylcholine (ACh) regulates NSC quiescence and differentiation within neurogenic niches, glioblastoma cells exploit these pathways to enhance their adaptability and invasiveness. The involvement of muscarinic (M3) and nicotinic (α7) receptors in both cell types suggests that glioblastoma retains neural progenitor-like traits, contributing to its plasticity and resilience. This article explores the shared cholinergic mechanisms between NSCs and GSCs, highlighting their role in both neural development and glioblastoma progression. Related Articles | Metrics

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G protein–coupled receptor 37 biomarker potential in Parkinson’s disease: Inflammation might be the hidden trigger Josep Argerich, Marc López-Cano, Francisco Ciruela 2026, 21 (7):  2938-2939.  doi: 10.4103/NRR.NRR-D-25-00581 Abstract ( 74 )   PDF (1243KB) ( 10 )   Save G protein–coupled receptor 37 (GPR37) is an orphan receptor predominantly expressed in the brain, particularly in oligodendrocytes and certain types of neurons. Notably, it has been shown that the N-terminal domain of GPR37 undergoes proteolysis under normal physiological conditions, resulting in the formation of cleaved receptor forms and the release of its ectodomain (ecto-GPR37) into the extracellular milieu (Mattila et al., 2021). Importantly, ecto-GPR37 density is increased in cerebrospinal fluid (CSF) of patients suffering from sporadic Parkinson’s disease (PD), together with an abnormal GPR37 processing in post-mortem PD substantia nigra (Morató et al., 2021; Figure 1A). Recently, we demonstrated that GPR37 density upregulation extends to other key brain regions, concretely the prefrontal cortex and striatum (Figure 1B), during the early stages of the disease, but not to other neurodegenerative disorders with overlapping symptoms, including c o r t i c o b a s a l d e g e n e r a t i o n , p r o g r e s s i v e supranuclear palsy, and multiple system atrophy (Argerich et al., 2024). However, the most striking finding was that the increase in GPR37 density was accompanied by elevated levels of CSF ecto-GPR37, observed exclusively in patients with slow-progressing PD. Thus, these results suggest that GPR37 has a differential regulation on PD pathology. Indeed, ecto-GPR37 might serve as a biomarker for predicting disease progression rates (Argerich et al., 2024). In summary, GPR37 has emerged as a potential marker for the postmortem stratification of neurodegenerative diseases, while ecto-GPR37 shows promise as a predictive biomarker for the progression of PD (Morató et al., 2021; Argerich et al., 2024). Related Articles | Metrics

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FKBP51: A new target for Parkinson’s disease Marta Garcia-Gomara, Mar Cuadrado-Tejedor, Ana Garcia-Osta 2026, 21 (7):  2940-2941.  doi: 10.4103/NRR.NRR-D-25-00651 Abstract ( 71 )   PDF (660KB) ( 52 )   Save Parkinson’s disease (PD) is a progressive age-related neurodegenerative disorder clinically defined by motor symptoms and pathologically by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta. These neurons are characterized by the presence of the cytoplasmic pigment neuromelanin (NM), and their degeneration is closely associated with the accumulation of α-synuclein (α-syn) into intraneuronal inclusions known as Lewy bodies (LBs), which represent a neuropathological hallmark of PD. Related Articles | Metrics

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Harnessing synaptic plasticity for sustained motor improvement in Parkinson’s disease Srdjan Sumarac, Nader Pouratian, Aryn H. Gittis, Luka Milosevic 2026, 21 (7):  2942-2943.  doi: 10.4103/NRR.NRR-D-25-00636 Abstract ( 81 )   PDF (1037KB) ( 16 )   Save Deep brain stimulation (DBS) is an established therapeutic intervention for people with Parkinson’s disease (PwPD) and is increasingly being utilized for other neurological disorders. Although effective in alleviating motor symptoms and reducing medication requirements, DBS has undergone minimal conceptual evolution and still relies on continuous high-frequency electrical stimulation. In Parkinson’s disease (PD), this persistent stimulation may cause adverse effects, including dysarthria, stimulation-induced dyskinesia, impulsivity, and mood alterations. Additionally, the continuous energy demand of current DBS systems accelerates battery depletion, necessitating more frequent battery charging or battery replacement surgeries, increasing risks, burden, and costs. Basic neuroscience research has long demonstrated that exogenous electrical stimulation can induce persistent changes to synaptic connections, known as longterm plasticity. This raises the question of whether continuous DBS could be replaced by stimulation paradigms leveraging plasticity for therapeutic effects that persist even after stimulation ceases. Such approaches have recently been demonstrated in Parkinsonian rodent models (Figure 1A and C) and PwPD (Figure 1B and D). In general, the field still lacks robust bench-to-bedside translation, with limited incorporation of mechanistic insights into clinical DBS protocols. A critical re-evaluation of existing DBS strategies, with an emphasis on harnessing lasting physiologically-informed plastic changes to modulate circuit function, may yield more effective therapeutic strategies that minimize stimulation-related side effects and energy demands to reduce therapeutic burden, risks, and costs. Related Articles | Metrics

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Reevaluating the role of skeletal muscle in amyotrophic lateral sclerosis pathogenesis: Insights from muscle-derived factors Pablo Martinez, Brigitte van Zundert, Fernando J. Bustos 2026, 21 (7):  2944-2945.  doi: 10.4103/NRR.NRR-D-25-00567 Abstract ( 68 )   PDF (478KB) ( 14 )   Save Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by motor neuron (MN) degeneration, neuromuscular junction disruption, and muscle atrophy, ultimately leading to paralysis and death. Despite extensive research, no effective treatment exists, highlighting the need to elucidate mechanisms driving ALS pathogenesis. Related Articles | Metrics

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From translation to stabilization and degradation: A multifaceted approach for the treatment of superoxide dismutase 1–associated amyotrophic lateral sclerosis. Christen G. Chisholm, Luke McAlary, Jeremy S. Lum 2026, 21 (7):  2946-2947.  doi: 10.4103/NRR.NRR-D-25-00778 Abstract ( 85 )   PDF (1187KB) ( 10 )   Save S u p e rox i d e d i s m u t a s e 1 ( S O D 1 ) i s a thermodynamically stable, zinc and copper binding homodimeric enzyme responsible for breaking down superoxide radicals. More than 200, mostly missense, mutations spread throughout the SOD1 gene are associated with the fatal neurodegenerative disease, amyotrophic lateral sclerosis (ALS). A unifying feature of ALS-associated SOD1 mutations is the destabilization of the SOD1 protein structure, increasing the propensity for misfolding and subsequent pathological aggregation. Post-mortem analysis of SOD1-associated ALS tissue shows the accumulation of misfolded SOD1 protein and ubiquitinated SOD1 inclusions within motor neurons. Misfolded SOD1 accumulation and aggregates are implicated in cellular dysfunction via a number of disparate but critical processes, including endoplasmic reticulum stress, oxidative damage, proteasome dysfunction, axonal transport abnormalities and synaptic dysfunction; culminating in motor neuron degeneration associated with ALS. As a result, misfolded and aggregated SOD1 is a primary target for therapeutic investigation in SOD1-associated ALS. Some of these approaches have shown preclinical and clinical promise, but often these therapies are targeted against a single component of disease. The cancer field has made great clinical strides utilizing a multi-pronged strategy to treat various forms of cancer. Patients are treated with a combination of multiple chemotherapy agents, radiation, surgery and/or immunotherapy to produce more effective therapeutic outcomes. In a similar manner, we propose that utilizing a multifaceted approach to target SOD1 across its pathogenic landscape may provide a highly feasible and more effective treatment approach. Related Articles | Metrics

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Adult central nervous regeneration in Drosophila: Evidence for glial lineage conversion and neurogenic potential post-injury Sergio Casas-Tintó, Maria Losada-Pérez 2026, 21 (7):  2948-2949.  doi: 10.4103/NRR.NRR-D-25-00768 Abstract ( 80 )   PDF (555KB) ( 8 )   Save Adult neurogenesis is generally considered to be very limited; however, there is increasing evidence that this phenomenon is conserved across species. Traditionally, research has focused on identifying precursor cells, those that are actively dividing or have the potential to divide. Direct evidence of adult neurogenesis has been found in rats, mice, songbirds, and nonhuman primates. In humans, while the evidence is indirect, it strongly suggests that neurogenesis also occurs during adulthood. In mammals, this active neurogenesis is preserved by radial glial progenitors, which remain in specific niches in the subventricular zone of the lateral ventricles and in the subgranular zone of the hippocampal dentate gyrus (Kumar et al., 2019). Related Articles | Metrics

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Glycine decarboxylase as a novel regulator of N-methyl-D-aspartate receptor function: Implications for pathophysiology of schizophrenia Maltesh Kambali, Uwe Rudolph 2026, 21 (7):  2950-2951.  doi: 10.4103/NRR.NRR-D-25-00318 Abstract ( 73 )   PDF (6122KB) ( 12 )   Save G l u t a m a t e r e c e p t o r s a n d s c h i z o p h r e n i a : Schizophrenia is a chronic mental disorder affecting approximately 1% of the global population, with 70%–80% heritability. It has a multifactorial etiology involving both environmental factors and a complex polygenic genetic architecture. Over the last two decades, large-scale genome-wide approaches revealed contributions of common variants with individually small effect sizes and of rare copy number variants with a large effect size. Related Articles | Metrics

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Pan-biological characteristics of ataxin-2 protein André Conceição, Clévio Nóbrega 2026, 21 (7):  2952-2953.  doi: 10.4103/NRR.NRR-D-25-00751 Abstract ( 85 )   PDF (769KB) ( 23 )   Save Ataxin-2 is a 140 kDa cytoplasmic multifunctional protein that plays fundamental roles in diverse cellular mechanisms (Costa et al., 2024). Although widely studied in the context of the neurodegenerative diseases spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS), ataxin-2 functions span far beyond its pathogenic properties in the disease context (Figure 1). In fact, it has a wide range of biological functions that include RNA metabolism, translation regulation, stress response, endocytosis, calcium signaling, and the control of circadian rhythm. In this perspective, we highlight the main roles of ataxin-2 protein, which are described in detail in Costa et al. (2024). Related Articles | Metrics

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Wolfram syndrome: A perspective on gene editing as a therapeutic strategy Steven Bergmans, Lies De Groef 2026, 21 (7):  2954-2955.  doi: 10.4103/NRR.NRR-D-25-00835 Abstract ( 74 )   PDF (2279KB) ( 5 )   Save Wolfram syndrome (WS) is a rare autosomal rece s s i ve disease characte r i zed by the development of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (often referred to as DIDMOAD), and overall severe neurodegenerative fallback. The global prevalence of this disease is estimated at 1 in 770,000 (Lee et al., 2023). It is most commonly caused by biallelic (point)mutations in the Wolframin endoplasmic reticulum (ER) transmembrane glycoprotein (WFS1) gene (in case of WS type 1), but mutations in the CDGSH Iron Sulfur Domain 2 (CISD2) are also linked to WS (type 2). The latter, however, often present with less severe pathological manifestations (Lee et al., 2023). WFS1 is located on chromosome 4p16.1 and spans over 33 kilobases. Many mutation variants have been identified in WFS1, encompassing missense, nonsense, and frameshift mutations. These mutations are spread across the coding region of WFS1, but certain regions, such as exon 8, the largest exon, appear particularly mutationprone and associated with the classical WS type 1 phenotype (Lee et al., 2023). Wolframin, the protein encoded by WFS1, is essential for ER calcium homeostasis, regulation of the unfolded protein response, and ensuring proper ERmitochondrial communication. Mutations in WFS1 that result in a loss-of-function, consequently lead to chronic ER stress and activation of apoptotic pathways, particularly in metabolically demanding cells such as pancreatic β-cells and neurons. As such, a spectrum of clinical manifestations arises in WS patients (Lee et al., 2023). The disease typically manifests during early childhood, beginning with diabetes and followed by progressive optic nerve atrophy, hearing loss, and various neurological and urological complications. Other symptoms may include psychiatric manifestations, sleep disturbances, ataxia, and cognitive decline. Life expectancy is significantly reduced, often due to brainstem atrophy and respiratory failure in the third to fourth decade of life (Lee et al., 2023). Related Articles | Metrics

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Melatonin reverses obesity-induced neurodegeneration through glymphatic restoration Bandy Chen 2026, 21 (7):  2956-2957.  Abstract ( 72 )   PDF (1905KB) ( 11 )   Save Obesity is characterized by both central and peripheral alterations, increasing the risk for neurological and metabolic disorders. Recent evidence indicate that obesity can disrupt the glymphatic system and impair the clearance of cerebrospinal fluid (CSF). This can lead to the build of neurotoxic molecules, potentially explaining obesity’s risk for neurodegeneration and cognitive decline. Given that glymphatic flow is tightly regulated by sleep, and that sleep disturbances are seen in obesity, melatonin emerges as a promising candidate to target glymphatic dysfunction in obesity. In both clinical and preclinical models, exogenous melatonin improves sleep quality and enhances slow-wave sleep, which is the sleep stage when glymphatic clearance is most active. This perspective aims to explore the mechanistic links between obesity and glymphatic dysfunction, highlighting melatonin as a novel therapeutic to mitigate cognitive and neurological consequences associated with obesity through the restoration of the glymphatic system. The mechanistic studies are predominantly based on animal models; therefore, additional human studies that explore the effect of melatonin on glymphatic function are much needed. Related Articles | Metrics

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Progranulin: Dose-dependent neurotoxicity Shinya Kusakari, Kohsuke Kanekura 2026, 21 (7):  2958-2959.  doi: 10.4103/NRR.NRR-D-25-00869 Abstract ( 83 )   PDF (2087KB) ( 8 )   Save Progranulin (PGRN), encoded by the GRN gene, is a secreted glycoprotein that undergoes proteolytic cleavage to generate individual granulin peptides (granulin A–G) capable of exerting distinct biological functions. PGRN is widely expressed in multiple tissues, including the central nervous and immune systems. Within the central nervous system, PGRN is highly expressed in the hippocampus, cerebral cortex, and hypothalamus, and has been detected in various neuronal subtypes, including Purkinje cells and motor neurons, where it plays a crucial role in neuronal functions, such as neurite outgrowth and synaptic plasticity. In addition to neurons, PGRN is expressed in glial cells, particularly in microglia, where it regulates phagocytosis. Furthermore, PGRN is presented in peripheral immune cells, including macrophages, and contributes to the regulation of inflammatory responses. PGRN exerts its diverse functions via binding partners, including receptors such as sortilin, EphA2, Notch, death receptor 3, and toll-like receptor 9 (Chitramuthu et al., 2017). These interactions underlie the involvement of PGRN in a wide range of cellular processes, including proliferation, differentiation, migration, immune regulation, and tumorigenesis. For instance, the interaction of PGRN with sortilin participates in the endocytosis and lysosomal trafficking of PGRN, whereas Notch signaling influences cell fate decisions and has implications for both neural development and oncogenesis (Chitramuthu et al., 2017). Related Articles | Metrics

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Proactively restore visual function: Directly targeting affected retinal neurons Ioannis Smyrnias, Ngan Pan Bennett Au 2026, 21 (7):  2960-2961.  doi: 10.4103/NRR.NRR-D-25-00860 Abstract ( 81 )   PDF (1311KB) ( 11 )   Save Our optic nerves are vulnerable to both traumatic and non-traumatic insults, rendering optic neuropathy a leading cause of permanent and irreversible visual impairment. Optic neuropathies can arise from hereditary [e.g., dominant optic atrophy (DOA) and Leber hereditary optic neuropathy (LHON)], ischaemic (e.g., anterior and posterior ischaemic optic neuropathy), inflammatory (e.g., optic neuritis), toxic (e.g., methanol, ethambutol) and nutritional (e.g., vitamin B12 deficiency), or traumatic conditions. Amongst these, glaucomatous optic neuropathy represents the most prevalent form and constitutes the second leading cause of blindness worldwide, with approximately 10% of patients developing bilateral blindness. Currently, over 76 million people are affected by glaucoma globally—a number predicted to rise to 112 million by 2040. Current treatments primarily focus on lowering intraocular pressure (IOP) through topical medications and surgical interventions. However, a recent study from the United Kingdom Glaucoma Treatment Study demonstrated that whilst IOP-lowering treatments effectively slow disease progression, they fail to reverse visual field deficits (Reddingius et al., 2025), underscoring the urgent need for novel therapeutic strategies that proactively restore visual function by directly targeting affected retinal neurons responsible for conveying visual information to the brain.   Related Articles | Metrics

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Translational value of understanding brain–spinal interactions in persistent pain Juhee Shin, Hyun Jun Jang, Boyoung Lee 2026, 21 (7):  2962-2963.  doi: 10.4103/NRR.NRR-D-25-00837 Abstract ( 79 )   PDF (890KB) ( 9 )   Save Neuropathic pain is a complex and debilitating condition caused by lesions or dysfunction within the somatosensory nervous system. Affecting an estimated 7%–10% of the global population, it presents with spontaneous pain, hyperalgesia, and allodynia, often accompanied by long-term emotional and cognitive consequences, such as depression and anxiety, which result in a reduced quality of life. Despite extensive research efforts, effective treatments remain limited. This limited efficacy likely stems, in part, from the heterogeneous nature of neuropathic pain, which varies widely across individuals in both clinical presentation and treatment responsiveness. To date, most preclinical studies have focused on localized changes in gene and protein expression, particularly within the spinal dorsal horn, offering only a partial view of the molecular processes sustaining pain. Related Articles | Metrics

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Aging epigenome begins to change in age-related neurodegenerative diseases Adam Zaretsky, Debra Toiber 2026, 21 (7):  2964-2965.  doi: 10.4103/NRR.NRR-D-25-00805 Abstract ( 79 )   PDF (939KB) ( 8 )   Save With the rapid increase in the aging population comes a rise in the incidence and prevalence of neurodegenerative diseases. Therefore, it is critical to understand the molecular changes that occur, which can either cause disease or make brains resilient. Epigenetic changes are a common suspect and target, not only because they are among the hallmarks of aging, but also because they are flexible and could potentially be reversed. Related Articles | Metrics

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Astrocytic ion channel Kir4.1 deficit underlies chronic pain Sarah Mountadem, Daniel L. Voisin, Radhouane Dallel 2026, 21 (7):  2966-2967.  doi: 10.4103/NRR.NRR-D-25-00773 Abstract ( 82 )   PDF (802KB) ( 12 )   Save While acute nociceptive pain is a crucial warning system that protects us from injury or disease, chronic pain is not protective, but a pathological condition. As such, it is now recognized as a disease in its own right, which major classes refer to inflammatory, neuropathic, and idiopathic pain. It is frequent, with up to a third of the population that may suffer at one point from chronic pain. It is often associated with other pathologies, including sleep disorders, anxiety, depression, and is still difficult to treat. It thus represents a significant burden in terms of health and societal impact (Tracey et al., 2019). The mechanisms of chronic pain involve multiple diverse pathways in both the peripheral and central nervous systems (CNS), reflecting its multifaceted biology. Indeed, research over the past decades has established that central sensitization (enhancement in the function of neurons and circuits in central nociceptive pathways), in particular within the dorsal horn, the first central relay of nociceptive inputs plays a key role in the chronicity of pain (Latremoliere and Woolf, 2009). Related Articles | Metrics

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Comparative analysis of chemical and lentiviral approaches in the generation of human induced pluripotent stem cell–derived motor neurons Masood Sepehrimanesh, Wu Xu, Baojin Ding 2026, 21 (7):  2968-2974.  doi: 10.4103/NRR.NRR-D-24-00435 Abstract ( 153 )   PDF (1424KB) ( 68 )   Save The generation of human induced pluripotent stem cell–derived motor neurons overcomes limited access to human tissues and offers an unprecedented approach to modeling motor neuron diseases such as dystonia and amyotrophic lateral sclerosis. Motor neurons generated through different strategies may exhibit substantial differences in purity, maturation, characterization, and even neuronal identity, leading to variable outcomes in disease modeling and drug screening. However, very few comparative studies have been conducted to determine the similarities and differences among motor neurons prepared via different protocols. In this study, we prepared human induced pluripotent stem cell–derived motor neurons via lentiviral delivery of transcription factors and chemical induction and performed a systematic comparative analysis. We found that motor neurons generated by both approaches showed typical motor neuron morphology and robustly expressed motor neuron-specific markers, such as nuclear homeobox transcription factor 9 and choline acetyltransferase. The chemical induction protocol utilizes a combination of small molecules to induce motor neuron differentiation, offering a significantly faster maturation time of 35 days compared to 46 days with lentiviral delivery of transcription factors. Additionally, while lentiviral delivery of transcription factors are suitable for downstream biochemical analysis, chemical induction are more applicable for therapeutic approaches as they avoid the use of lentiviruses. Both approaches produce motor neurons with high purity (> 95%) and yield. No significant differences were found between chemical induction and lentiviral delivery of transcription factors in terms of motor neuron markers and maturation markers. These robust methodologies offer researchers powerful tools for investigating motor neuron diseases and potential therapeutic strategies. Related Articles | Metrics

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Microglial CARD19 ameliorates post-stroke neuroinflammation by stabilizing mitochondrial cristae Yujie Hu, Liwen Zhu, Chao Zhou, Qi Li, Huiya Li, Shiji Deng, Shengnan Xia, Haiyan Yang, Xinyu Bao, Pinyi Liu, Yun Xu 2026, 21 (7):  2975-2985.  doi: 10.4103/NRR.NRR-D-24-00923 Abstract ( 163 )   PDF (6996KB) ( 35 )   Save Microglia are the first immune cells that are activated in the brain following ischemic stroke. Mitochondrial dysfunction exacerbates microglia-mediated neuroinflammation post-stroke. Caspase activation and recruitment domain 19 (CARD19) is involved in innate immune response and inflammatory response, which are also important functions of microglia. However, the role of CARD19 in microglial biology and ischemic stroke remains unknown. Here, we observed that CARD19 expression was significantly elevated in microglia in the penumbra after ischemic stroke via analyzing the spatial transcriptomic sequencing data of ischemic brain tissue, as well as in an in vitro model of microglial activation. Remarkably, conditional knockdown of Card19 in microglia promoted poststroke neuroinflammation and worsened neurological outcomes in a mouse model of ischemic stroke. Mechanistically, we found that CARD19 localized to mitochondria and promoted the assembly of mitochondrial intermembrane bridge components, while CARD19 deficiency in microglia caused ultrastructural and functional damage to the mitochondrial cristae, leading to an exaggerated pro-inflammatory response. Thus, our findings suggest that preserving mitochondrial cristae, by targeting CARD19 could be a novel therapeutic strategy for ameliorating neuroinflammation post-stroke and decreasing the volume of the ischemic penumbra. Related Articles | Metrics

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Chemerin 15 peptide reduces neuroinflammation via the ChemR23 receptor after ischemia–reperfusion injury Yan Huang, Shuang Li, Yuhan Yang, Kunyi Li , Lan Wen, Jinglun Li 2026, 21 (7):  2986-2996.  Abstract ( 120 )   PDF (11852KB) ( 13 )   Save Microglia-mediated neuroinflammation plays a crucial role in ischemic stroke; consequently, understanding its regulation could facilitate the development of therapies for ischemic stroke. Chemerin 15, a 15-amino acid peptide derived from chemerin, exerts powerful anti-inflammatory effects through ChemR23, modulates macrophage polarization, and diminishes inflammatory cytokine expression in peripheral inflammation models. However, its effects on microglia and stroke remain unclear. In this study, we used an in vitro oxygen/glucose deprivation BV2 cell model and a mouse model of ischemia-reperfusion injury to investigate the role of chemerin 15 in stroke and the underlying mechanisms. We co-cultured BV2 microglial cells with HT-22 hippocampal neurons and observed that chemerin 15 reduced apoptosis in HT-22 cells. Furthermore, we found that chemerin 15 binds to the ChemR23 receptor on the cell surface, inducing its internalization. This process regulated the activity of adenosine 5ʹ-monophosphate-activated protein kinase and inhibited its downstream target nuclear factor kappa B. These effects could be reversed by treatment with α-NETA, a ChemR23 inhibitor. In mice with ischemia-reperfusion injury, chemerin 15 modulated microglial polarization, reduced infarct volume and neuronal apoptosis, and facilitated cognitive and neurological function recovery. Our findings suggest that chemerin 15 suppresses the microglia-mediated inflammatory response, decreases neuronal apoptosis, and enhances long-term neurological function recovery by inducing ChemR23 internalization and regulating the adenosine 5ʹ-monophosphate-activated protein kinase/nuclear factor kappa B signaling pathway. Related Articles | Metrics

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Lycium barbarum glycopeptide reduces brain damage following ischemic stroke by inhibiting ferroptosis and oxidation Wei Zhang, Moushen Tang, Yujie Wang, Yongxia Huang, Zhexiong Yu, Lihui Zhu, Jian Wang, Kwok-Fai So, Yiwen Ruan 2026, 21 (7):  2997-3006.  Abstract ( 169 )   PDF (3751KB) ( 90 )   Save Recent studies have indicated that stroke can lead to neuronal iron overload and lipid peroxidation. Lycium barbarum glycopeptide, which has a low molecular weight and potent antioxidant properties, may mitigate ferroptosis in stroke. We hypothesized that Lycium barbarum glycopeptide can effectively mitigate iron overload within ischemic neurons due to its robust antioxidant properties. The aims of this study were to investigate the effects of Lycium barbarum glycopeptide on ferroptotic damage following brain ischemia and explore the underlying mechanisms. A rat model of middle cerebral artery occlusion was established using the intraluminal filament method, and the rats were treated with Lycium barbarum glycopeptide for 7 consecutive days, beginning 24 hours after ischemia. Liproxstatin-1, a ferroptosis inhibitor, and Erastin, a ferroptosis activator, were used as controls. We found that treatment with Lycium barbarum glycopeptide resulted in significant reductions in infarct volume (as detected by triphenyltetrazolium chloride staining staining and magnetic resonance imaging) and neuronal death (as measured by Nissl staining), as well as improvements in sensory and motor functions in rats subjected to middle cerebral artery occlusion. Furthermore, treatment with Lycium barbarum glycopeptide alleviated anxiety and depression-like behaviors and improved memory. Additionally, Lycium barbarum glycopeptide effectively reduced the iron ion content in the ischemic penumbra of the cortex. Moreover, treatment with Lycium barbarum glycopeptide downregulated the expression of ferroptotic and oxidant proteins such as transferrin receptor 1, divalent metal transporter 1, and Acyl-CoA synthetase long-chain family member 4 and upregulated the expression of anti-ferroptotic and antioxidant proteins such as ferroportin 1, solute carrier family 7 member 11, glutathione, and glutathione peroxidase 4. However, these beneficial effects were reversed when ferroptosis was induced with the activator Erastin. Therefore, the positive effects of Lycium barbarum glycopeptide in ischemic stroke are likely mediated through activation of the antiferroptotic pathway and the antioxidative System Xc-glutathione-glutathione peroxidase 4 pathway. Overall, our findings highlight the potential use of Lycium barbarum glycopeptide as a neuroprotective agent targeting both ferroptosis and oxidation to decrease ischemic brain damage. Related Articles | Metrics

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Macrophages-derived NRG-1 promotes angiogenesis after ischemic stroke via the Akt-mTOR pathway. Jie Chen, Bo Wang, Danyang Fan, Xi Chen, Lenv Gao, Yun Luo, Zhenhua Zhou 2026, 21 (7):  3007-3016.  doi: 10.4103/NRR.NRR-D-24-01323 Abstract ( 73 )   PDF (10982KB) ( 4 )   Save Acute ischemic stroke remains a significant health concern owing to the limited efficacy of current therapeutic options. In recent years, Neuregulin-1 has exhibited promising neuroprotective effects in cerebral ischemia. However, the sources and functions of Neuregulin-1 have not yet been fully understood, which hinders its translation and broad application. Here, we collected paired clot and peripheral blood samples from patients with acute ischemic stroke to determine the sources of Neuregulin-1. In addition, we established an in vivo transient middle cerebral artery occlusion mouse model to investigate the therapeutic effects of Neuregulin-1 and its underlying molecular biological mechanisms. We observed a significant elevation in serum Neuregulin-1 levels among patients with acute ischemic stroke that correlated with severity of neurological impairment and clinical outcome. Using single-cell sequencing, we identified Neuregulin-1-positive macrophages among peripheral blood mononuclear cells that produced Neuregulin-1 postischemia. In addition, Neuregulin-1 promoted repair of the infarcted area, alleviating neuronal and myelin damage and improving overall behavioral recovery in mice. We found that Neuregulin-1 may exert these neuroprotective effects by promoting angiogenesis in the infarct area, and that this effect is mediated by Akt/mTOR/VEGF-dependent signaling. Our findings suggest that peripheral macrophages are a source of Neuregulin-1 post-stroke. Neuregulin-1 exerts its neuroprotective effects by promoting angiogenesis via Akt/mTOR/VEGF-dependent signaling, showing promising clinical translation potential. Related Articles | Metrics

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An innovative treatment for hypoxic–ischemic encephalopathy: Silk fibroin nanomaterials improve neural stem cell axon formation and facilitate cognitive improvement Chao Han, #, Shuna Chen, Zihan Shi, Xin Guan, Wei Zou, Jing Liu 2026, 21 (7):  3017-3025.  doi: 10.4103/NRR.NRR-D-24-01178 Abstract ( 74 )   PDF (8583KB) ( 6 )   Save Stem cell therapy shows promise for treating brain injuries; neural stem cells in particular are capable of repairing damage by forming new nerve cells and supporting recovery. However, optimizing the implantation and functionality of these cells in damaged brain regions remains challenging. Silk fibroin, a natural protein derived from silkworm silk, is a biocompatible material with exceptional properties that are useful for tissue engineering. Its biodegradability, mechanical robustness, and ability to promote cell growth make it particularly valuable for biomedical applications. Silk fibroin nanomaterials, which comprise silk fibroin processed into nanostructures, offer enhanced surface area, improved loading capacity for bioactive molecules, and superior nanoscale interactions with cells compared with bulk silk fibroin materials. In this study, we first extracted human-derived neural stem cells from a 14-week-old human fetus. Then, neural stem cells were loaded with 1% silk fibroin nanomaterials, which was identified as the optimal concentration to support human-derived neural stem cell growth and release of neurotrophic factors. Finally, 1% silk fibroin nanomaterials were implanted into a rat model of hypoxic-ischemic brain injury. The results showed that, compared with the treatment with human-derived neural stem cells alone, silk fibroin hydrogel carrying human-derived neural stem cells was significantly more effective at alleviating brain tissue damage, increasing neurotrophic factor secretion in the brain microenvironment, and promoting motor and cognitive function recovery. These findings suggest that silk fibroin nanomaterials loaded with human-derived neural stem cells could be used to treat hypoxic-ischemic ncephalopathy. However, the mechanisms and related signaling pathways by which hydrogels combined with cells exert their reparative effects still require further in-depth investigation. Related Articles | Metrics

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Investigating the correlation between neural and muscular activities during bilateral arm training in stroke survivors: A cross-sectional study Yan Tang, Tara Scarlette Rosalyn Chen, Yi Xu, Pu Wang, Peng Dou, Dongfeng Huang 2026, 21 (7):  3026-3034.  doi: 10.4103/NRR.NRR-D-24-01279 Abstract ( 70 )   PDF (34873KB) ( 16 )   Save Stroke patients experience varying degrees of upper limb functional impairment. Although bilateral arm training can help stroke patients recover movement after stroke, little is known about the way in which the brain and muscles work together during this type of training. To address this, we conducted a cross-sectional study at The Seventh Affiliated Hospital, Sun Yat-sen University in China, where we observed the connection between brain and muscle activity during bilateral upper limb training in 21 stroke patients and 17 healthy controls. We used functional near-infrared spectroscopy and surface  electromyography to measure changes in cerebral cortex oxygenation and upper limb muscle contraction signals, respectively. The results showed that, compared with the healthy control group, stroke patients had reduced functional connectivity and more irregular muscle activity in the affected flexor muscle during bilateral upper limb training. Moreover, we found a significant correlation between the surface electromyographic signal characteristics of upper limb muscles and cerebral oxygenation indicators of multiple brain regions in stroke patients. These findings indicate that bilateral upper limb training is an effective rehabilitation method that improves upper limb motor function in stroke patients by promoting brain functional connectivity and improving muscle activity patterns. Related Articles | Metrics

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NeuroD1-based in situ neural regeneration for the treatment of radiation-induced brain injury Xudong Yan, Ke Zhong, Meijuan Zhou, Jiao Chen, Yajie Sun, Yamei Tang, Gong Chen, Yongteng Xu 2026, 21 (7):  3035-3045.  doi: 10.4103/NRR.NRR-D-24-01067 Abstract ( 151 )   PDF (46542KB) ( 26 )   Save Radiation-induced brain injury remains one of the most severe complications of radiotherapy for head and neck tumors, with limited options for prevention and treatment. In situ neural regeneration technology has demonstrated promising therapeutic effects in various neurodegenerative and neurotrauma conditions. In this study, we overexpressed the neural transcription factor NeuroD1 using in situ neural regeneration technology in a radiation-induced brain injury mouse model. This approach converted reactive astrocytes into neurons, increased neuronal density, protected endogenous neurons, decreased microglial activation, reduced peripheral CD8+ T cell infiltration, and diminished angiogenesis in the injured area, leading to a significant reduction in lesion volume. Additionally, we explored the potential mechanisms of NeuroD1 in situ neural regeneration technology through bulk RNA sequencing, which showed an upregulation of neurogenesis-related genes and a downregulation of immune response–related and angiogenesis-related genes. Furthermore, our findings suggested that NeuroD1 in situ neural regeneration technology converted reactive astrocytes into neurons and reduced microglial activation in a thalamic hemorrhagic stroke mouse model. In summary, this study supports NeuroD1 in situ neural regeneration technology as a potential therapeutic approach for treating radiationinduced brain injury and hemorrhagic stroke, and offers new insights into the therapeutic role of NeuroD1 in delayed brain injury. Related Articles | Metrics

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Lactate alleviates early brain damage after subarachnoid hemorrhage: Regulation of lipid metabolism Zichen Zhang, Xinan Li, Xiaoli Liu, Lei Chen, Yunzhi Wang, Enyan Jiang, Jia Zeng, Xiaojian Zhang, Zhen Fang, Zibin Liang, Jikai Wang, Fei Liu 2026, 21 (7):  3046-3054.  doi: 10.4103/NRR.NRR-D-24-01543 Abstract ( 101 )   PDF (119587KB) ( 30 )   Save This study investigated the neuroprotective effects of lactate in subarachnoid hemorrhage, a severe cerebrovascular disease that is commonly caused by arterial aneurysm rupture and has limited early treatment options. Lactate, a metabolic byproduct, has been shown to have neuroprotective properties, including enhancing cerebral microcirculation and reducing intracranial pressure in acute brain injury patients. However, the protective mechanisms of lactate in subarachnoid hemorrhage remain unknown. In this study, we showed that lactate alleviates early brain damage in subarachnoid hemorrhage by promoting neuronal lipid synthesis and the formation of lipid droplets in astrocytes. In vivo experiments using a subarachnoid hemorrhage mouse model showed that lactate treatment significantly improved neurological scores, reduced brain inflammation, and promoted lipid droplet formation in astrocytes within 24 hours. Lactate treatment increased free fatty acids levels in the brain. The results suggest that astrocytes absorbed these free fatty acids and converted them into lipid droplets, thus reducing cellular lipotoxicity. Moreover, lactate enhanced the antiapoptotic capacity of astrocytes by upregulating the expression of PLIN5, a protein crucial for lipid droplet formation. The inhibition of lipid synthesis or lipid droplet formation counteracted the neuroprotective effects of lactate, indicating that lactate’s protective role is closely linked to lipid metabolism and lipid droplet formation. In vitro experiments on HT22 neuronal cells exposed to hemin—an agent used to simulate subarachnoid hemorrhage injury—demonstrated that lactate mitigated cellular damage by reducing lipid peroxidation and preserving mitochondrial membrane potential. Lactate treatment in HT22 cells and astrocytes also showed that inhibition of lipid synthesis or lipid droplet formation reversed its protective effects, further emphasizing the importance of lipid metabolism in the neuroprotective action of lactate. This study provides insights into the neuroprotective mechanisms of lactate in subarachnoid hemorrhage. It indicates that lactate plays a role in promoting lipid synthesis in neurons and enhancing lipid droplet formation in astrocytes, thus mitigating brain damage and improving cell survival. These findings suggest that lactate, through its regulation of lipid metabolism, could be a potential therapeutic agent for subarachnoid hemorrhage. Related Articles | Metrics

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Telomere length as a predictive marker for long-term cognitive function in a mouse model of subarachnoid hemorrhage  Qia Zhang, Chaoran Xu, Jiayong Fan, Chengjian Lou, Jiarui Chen, Jianmin Zhang, Jun Mo 2026, 21 (7):  3055-3062.  doi: 10.4103/NRR.NRR-D-24-01150 Abstract ( 85 )   PDF (10800KB) ( 16 )   Save Subarachnoid hemorrhage is a subtype of stroke that causes severe neurological damage and is associated with poor long-term prognosis. Cognitive impairment is a major manifestation of long-term neurological dysfunction in patients with subarachnoid hemorrhage. However, there is notable absence of biological markers to predict long-term prognosis in this patient population. Given the aging-like neurocognitive phenomena associated with subarachnoid hemorrhage, this study postulates that telomere length, a recognized biomarker for aging, could be used as a prognostic indicator for subarachnoid hemorrhage. A left internal carotid artery intravascular puncture mouse model was used to simulate subarachnoid hemorrhage. Comprehensive neurological test scores were obtained through neurobehavioral assessments conducted at one-month intervals. Concurrently, the relative telomere length was analyzed by quantitative polymerase chain reaction, which was performed using DNA extracted from ear notch and brain tissue after each assessment. Furthermore, proteomic analysis was employed to investigate differential protein expression in hippocampal tissue. Subarachnoid hemorrhage mice exhibited persistent neurocognitive impairment over a prolonged period of time. There was a significant positive correlation between telomere length and neurological test scores, confirming the usefulness of telomere length as a prognostic indicator in subarachnoid hemorrhage. Hippocampal tissue from subarachnoid hemorrhage mice showed reduced expression of acetyl-coenzyme A synthetase-2 and abnormalities in the expression of proteins related to ribosomes, energy metabolism, and cellular signal transduction. This study confirmed telomere shortening in the brain and metabolic disturbances in the hippocampi of subarachnoid hemorrhage mice. Thus, telomere length is a predictive marker for long-term impairment of cognitive function in mice following experimental subarachnoid hemorrhage. Related Articles | Metrics

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MDM2–GPX4–ferroptosis regulatory axis exerts neurotoxic effects in intracerebral hemorrhage Yunhu Yu, Tao Liu, Yunpeng Cai, Yuanmei Song, Hang Zhou , Fang Cao, Rongcai Jiang 2026, 21 (7):  3063-3072.  doi: 10.4103/NRR.NRR-D-25-00030 Abstract ( 169 )   PDF (3723KB) ( 64 )   Save Ferroptosis plays a key role in nerve injury in intracerebral hemorrhage and is associated with the upregulation of murine double minute 2. Investigating the mechanism underlying murine double minute 2-related ferroptosis could help identify new therapies for intracerebral hemorrhage. An in vitro intracerebral hemorrhage model was established by treating BV2 microglial cells with oxygen–glucose deprivation combined with hemin. The role of murine double minute 2 in regulating ferroptosis was investigated via transduction with RNA interference and lentivirus overexpression. Furthermore, intracerebral hemorrhage mouse models were constructed with and without an murine double minute 2 inhibitor (brigimadlin), and behavioral assays were performed to assess the learning ability and cognitive function. Murine double minute 2 dysregulation was associated with oxygen–glucose deprivation combined with hemin-induced BV2 microglial cell ferroptosis and M1/M2 polarization. The results suggested that murine double minute 2 induced glutathione peroxidase 4 ubiquitination and degradation to regulate ferroptosis and inflammatory responses in BV2 microglial cells. Mechanistically, Wilms tumor 1-associated protein induced murine double minute 2 N6-methyladenosine (m6A) modification and regulated ferroptosis and inflammatory responses. In vivo analysis showed that brigimadlin improved neurological deficits and spatial memory in mice with intracerebral hemorrhage. In summary, the results indicate that Wilms tumor 1-associated protein regulates murine double minute 2 m6A modification, and murine double minute 2 induces glutathione peroxidase 4 ubiquitination and degradation. This regulation promotes ferroptosis and inflammatory responses in oxygen–glucose deprivation combined with hemin-induced BV2 microglial cells, suggesting that the murine double minute 2–glutathione peroxidase 4–ferroptosis regulatory axis exerts neurotoxic effects. These findings identify glutathione peroxidase 4 as a potential gene therapy target for intracerebral hemorrhage–related brain injury. Related Articles | Metrics

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The intrinsic excitability of and autophagy protein expression levels in dentate gyrus ensembles regulate fear generalization Qing Lin, Tao Jin, Yang Yang, Xutian Hou, Ruyan Chen, Lan Ma, Xing Liu, Feifei Wang 2026, 21 (7):  3073-3082.  doi: 10.4103/NRR.NRR-D-24-01026 Abstract ( 105 )   PDF (5930KB) ( 25 )   Save The overgeneralization of fear is associated with psychiatric disorders and cognitive decline. Recent studies have shown that engram cells in the dorsal dentate gyrus are integrated into functionally heterogeneous ensembles that are involved in contextual fear memory generalization and discrimination. However, the intracellular signals that promote fear generalization remain to be fully elucidated. In this study, we labeled and manipulated the c-Fos+ and Npas4+ ensembles in the dorsal dentate gyrus that are activated by contextual fear conditioning using a robust activity marking system. The results showed that increasing the excitability of Fos-dependent robust activity marking by overexpressing NaChBac or decreasing the excitability of Npas4-dependent robust activity marking by overexpressing Kir2.1 promoted fear memory generalization. Furthermore, CRISPR-mediated downregulation of the autophagy-related Atg5 or Atg7 genes in dorsal dentate gyrus neurons inhibited activation of c-Fos, but not Npas4. Knockdown of Atg5 or Atg7 in the Fos-dependent robust activity marking or Npas4-dependent robust activity marking ensemble led to an increase in neuronal excitability and a decrease in spine density in both ensembles. However, Atg7 knockdown in the Fos-dependent robust activity marking ensemble promoted memory generalization, while knockdown of Atg5 or Atg7 in the Npas4-dependent robust activity marking ensemble increased anxiety levels. These results contribute to our understanding of how the varying plasticity of memory engrams is involved in regulating fear memory generalization and anxiety. Related Articles | Metrics

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Dual adeno-associated virus system for selective and sparse labeling of astrocytes Mei Li, Zhuang Liu, Ruixi Chen, Ziyue Zhao, Qingqing Zhou, Ning Zheng, Jie Wang, Hanbing Wang 2026, 21 (7):  3083-3091.  doi: 10.4103/NRR.NRR-D-24-01607 Abstract ( 85 )   PDF (23689KB) ( 7 )   Save Astrocytes are the most abundant glial cells in the central nervous system. They perform a diverse array of functions, with a critical role in structural integrity, synapse formation, and neurotransmission. These cells exhibit substantial regional heterogeneity and display variable responses to different neurological diseases. Such diversity in astrocyte morphology and function is essential for understanding both normal brain function and the underlying mechanisms of neurological disorders. To investigate this heterogeneity, we developed a novel method for the selective and sparse labeling of astrocytes in various brain regions. This technique utilizes a dual adeno-associated virus system that allows for the expression of Cre recombinase and enhanced green fluorescent protein under the control of the glial fibrillary acidic protein (GfaABC1D) promoter. The system was tested in C57BL/6J mice and successfully labeled astrocytes across multiple brain regions. The method enabled the detailed visualization of individual astrocytes—including their intricate peripheral processes—through three-dimensional reconstructions from confocal microscopy images. Furthermore, the labeling efficiency of this dual adeno-associated virus technology was validated by examining astrocyte function in a spared nerve injury model and through chemogenetic modulation. This innovative approach holds great promise for future research because it enables a more comprehensive understanding of astrocyte variation not only in spared nerve injury but also in a broad spectrum of neurological diseases. The ability to selectively label and study astrocytes in different brain regions provides a powerful tool for exploring the complexities of these essential cells and their roles in physiological and pathological conditions. Related Articles | Metrics

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Trans-spinal magnetic stimulation upregulates microglial SOCS3 to attenuate neuroinflammation in chronic constriction injury–induced neuropathic pain Qi Wu, Xingjun Xu, Chenyuan Zhai, Jili Cai, Zun Wang, Lu Fang, Yu Wang, Yilun Qian, Manyu Dong, Liang Hu, Tong Wang, Ying Shen, Wentao Liu 2026, 21 (7):  3092-3102.  doi: 10.4103/NRR.NRR-D-24-00912 Abstract ( 84 )   PDF (9374KB) ( 24 )   Save Current treatments for neuropathic pain are suboptimal, necessitating the search for more effective therapeutics. Our previous study showed that inhibition of neuroinflammation in the spinal cord induced analgesic effects, and focal repetitive trans-spinal magnetic stimulation showed an anti-neuroinflammatory effect in spinal cord injury rat models. Here, we speculated that repetitive trans-spinal magnetic stimulation might induce an anti-inflammatory effect to alleviate neuropathic pain by upregulating calmodulin-dependent protein kinase kinase beta (CaMKKβ)/adenosine 5′-monophosphate-activated protein kinase (AMPK)/suppressor of cytokine signaling-3 (SOCS3) signaling in microglia. Experiments have found that non-invasive focal repetitive trans-spinal magnetic stimulation effectively alleviates mechanical allodynia and spinal neuroinflammation in rats with neuropathic pain induced by chronic sciatic nerve ligation. Further research found that repetitive trans-spinal magnetic stimulation upregulated the expression of SOCS3 in spinal microglia, which subsequently inhibited the phosphorylation of p38 mitogen-activated protein kinase and signal transducer and activator of transcription 3 and nuclear factor-kappa B p65 nuclear translocation in rats with neuropathic pain, thereby suppressing neuroinflammation. The upregulation of SOCS3 by repetitive trans-spinal magnetic stimulation may be achieved through the activation of the CaMKKβ/AMPK signaling pathway in microglia. The results suggested that focal repetitive trans-spinal magnetic stimulation inhibits spinal neuroinflammation and alleviates neuropathic pain by activating the CaMKKβ/AMPK/SOCS3 signaling pathway in spinal microglia. This mechanism provides an effective noninvasive treatment for neuropathic pain caused by peripheral nerve injury.    Related Articles | Metrics

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Generation of humanized spinal astrocytic chimeric rat spinal cord model by engrafting human dorsal spinal neural stem/progenitor cells Wenjie Xu, Ziyu He, Jia Xu, Ruoying Zhang, Shu Fan, Zhixian Liu, Wei Wang, Hong Chen, Xiaolong Zheng 2026, 21 (7):  3103-3113.  doi: 10.4103/NRR.NRR-D-24-01176 Abstract ( 100 )   PDF (19819KB) ( 10 )   Save In the human spinal cord, astrocytes are the major glial cells. In vitro studies of human astrocytes are relatively simple. However, the straightforward nature of the in vitro environment and complex nature of the in vivo environment limit comprehensive investigations into the structure and function of human astrocytes. Additionally, in vivo studies of human astrocytes are further limited by ethical issues. This means there is an urgent need to develop effective in vivo models to study the structure and function of human astrocytes. Here, we first directed human embryonic stem cells to differentiate into human spinal cord dorsal neural stem/progenitor cells in vitro, before transplanting these cells into the gray matter of the cervical spinal cord (C5–T2 segments) of naïve nude rats to create a chimeric human astrocytic rat spinal cord model. The transplanted human spinal cord dorsal neural stem/ progenitor cells survived for at least 20 months in the spinal cord environment of the rats, with over 90% differentiating into human astrocytes. These human astrocytes were able to migrate caudally for long distances along the white matter towards the spinal cord. They expressed astrocytic cytoskeletal proteins and functionally-related proteins, suggesting their maturation and structural integration into the rat spinal cord. Thus, this humanized astrocyte chimeric rat spinal cord model provides a valuable tool for studying the role of human spinal cord astrocytes in various spinal diseases.  Related Articles | Metrics

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Targeting JNK1 mediates alleviation of neuroinflammation and promotes neural repair by cerebral dopamine neurotrophic factor after spinal cord injury Yanxiao Xiang, Pengchao Du, Yayun Zhang, Hao Li, Songgang Wang, Xianlei Gao, Xin Pan, Hua Zhao 2026, 21 (7):  3114-3121.  doi: 10.4103/NRR.NRR-D-24-00890 Abstract ( 78 )   PDF (4373KB) ( 10 )   Save Previous studies have shown that endoplasmic reticulum stress induces neuronal apoptosis, necrosis, and pro-inflammatory microenvironment after spinal cord injury. The JNK pathway is activated by endoplasmic reticulum stress and reactive oxygen species. Our previous research demonstrated that cerebral dopamine neurotrophic factor has anti-inflammatory effects and promotes the repair of the damaged spinal cord after injury. However, the molecular mechanism remains unclear. In this study, we found that cerebral dopamine neurotrophic factor binds JNK1 and regulates JNK1/2-c-Jun-p53 signaling in lipopolysaccharide-induced microglia. Cerebral dopamine neurotrophic factor also alleviated neuroinflammation by reducing the secretion of pro-inflammatory cytokines. Overexpression of cerebral dopamine neurotrophic factor in a mouse model of spinal cord injury promoted nerve regeneration and motor function recovery. These findings indicate the possibility for cerebral dopamine neurotrophic factor treating spinal cord injury by targeting the JNK1/2-c-Jun-p53 pathway.  Related Articles | Metrics

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Total flavonoids and nerve growth factor loaded gelatin-ginipin hydrogel for NIR enhanced spinal cord injury repair via inhibiting NF-κB pathway Yu Liang, Deshuang Xi, Yilin Teng, Pan Liu, Yanbing Feng, Qiumei Huang, Ming Gao, Shaohui Zong 2026, 21 (7):  3122-3129.  doi: 10.4103/NRR.NRR-D-24-01445 Abstract ( 73 )   PDF (8008KB) ( 6 )   Save Rat nerve growth factor and total flavonoids from hawthorn leaf contribute to the recovery of neurological function after spinal cord injury, including traumatic, non-traumatic spinal cord injuries. However, it remains challenging to efficiently deliver nerve growth factor and total flavonoids from hawthorn leaf to spinal cord injury sites, ensure their sustained release, and minimize further damage. In the present study, we chose a biocompatible and biodegradable gelatin as the substrate, which was crosslinked with the natural biological crosslinker genipin to form a gelatin–genipin hydrogel carrier for the slow release of nerve growth factor and total flavonoids from hawthorn leaf in spinal cord injury sites. The prepared gelatin–genipin hydrogel had good injectable properties and photothermal effects. Furthermore, when the hydrogel with 2% genipin, 200 ng/mL nerve growth factor, and 320 μg/mL total flavonoids from hawthorn leaf was combined with near infrared irradiation, there was a slow release of total flavonoids from hawthorn leaf and nerve growth factor, reduced oxidative stress, an improved inflammatory microenvironment, and accelerated angiogenesis and axonal regeneration via inhibition of the nuclear factor kappa-B signaling pathway, thereby promoting recovery from spinal cord injury. Collectively, our results indicate that this new hydrogel may improve the prognosis of spinal cord injury, and may represent a new strategy for treating spinal cord injury. Related Articles | Metrics

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Neuronal DJ-1 regulates microglia activation via ADAM10-mediated CX3CL1 secretion in Parkinson's disease Aonan Zhao, Yanfei Ding, Min Zhong, Mengyue Niu, Lingbing Wang, Yang Jiao, Jun Liu, Yuanyuan Li 2026, 21 (7):  3130-3138.  doi: 10.4103/NRR.NRR-D-24-01047 Abstract ( 81 )   PDF (9593KB) ( 7 )   Save DJ-1, also known as Parkinson’s disease protein 7 (PARK7), is a multifunctional protein that plays an important role in oxidative stress regulation and neuroprotection. Previous studies have shown that DJ-1 affects early-onset Parkinson’s disease by regulating neuroinflammation, but its specific mechanism remains unclear. The study investigated the role of DJ-1 in mediating microglia–neuron communication to identify potential therapeutic targets for neuroinflammation in Parkinson’s disease. In this study, we observed a significant decrease in the levels of C-X3-C motif chemokine ligand 1 (CX3CL1) in Park7 knockout mice and SH-SY5Y cells with Park7 knockdown. Protein microarray analysis and validation using GEO datasets confirmed that knockout of the Park7 gene led to downregulation of CX3CL1 and two other chemokines, namely monocyte chemoattractant protein-1 and interleukin-8. Further investigation revealed that Park7 deficiency reduced the processing of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in the neuronal endoplasmic reticulum of both mice and SH-SY5Y cells, thereby decreasing CX3CL1 secretion. This subsequently led to abnormal microglial activation, with a shift toward the proinflammatory M1 phenotype, exacerbating neuroinflammatory responses. These effects were mitigated by exogenous CX3CL1 administration. Concurrently, exogenous CX3CL1 improved motor function in Parkinson’s disease model mice with the Park7 knockout, promoting survival of tyrosine hydroxylase-positive neurons in the substantia nigra and reducing Iba-1-positive microglial activation. These findings demonstrate that DJ-1 exerts neuroprotective effects on dopaminergic neurons by suppressing microglial activation through CX3CL1 regulation, suggesting that targeting the DJ-1/CX3CL1 axis may represent a novel therapeutic strategy for modulating neuroinflammation and protecting dopaminergic neurons.  Related Articles | Metrics

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Circadian transcriptomic disruptions in the hippocampus precede cognitive deficits in an Alzheimer’s mouse model Anlin Qi, Yuxian He, Feng Zhang, Shiyan Liu, Qiuan Xiang, Yanqiong Dong, Bin Wang, Yingying Zhao 2026, 21 (7):  3139-3148.  doi: 10.4103/NRR.NRR-D-25-00851 Abstract ( 87 )   PDF (24326KB) ( 10 )   Save Mounting evidence suggests that circadian rhythm disruption may be linked to the onset and progression of Alzheimer’s disease. However, whether this disruption occurs before the appearance of cognitive symptoms and whether it drives disease development remain unclear. Understanding the temporal relationship between circadian rhythm dysregulation and early Alzheimer’s disease pathological changes may open up new avenues for disease prevention and intervention. To determine if circadian rhythm disruption precedes cognitive decline, we conducted high-resolution transcriptome analyses of the hippocampus in a 5-month-old mouse model of Alzheimer’s disease and age-matched wild-type control mice at multiple time points over a 24-hour period. While the mouse model of Alzheimer’s disease did not exhibit obvious cognitive symptoms at this stage, the expression of circadian-related genes in the hippocampus exhibited extensive abnormalities. In the control group, 2109 genes exhibited rhythmic expression characteristics. In the mouse model of Alzheimer’s disease, a marked proportion of these genes lost their rhythmicity, some genes newly developed rhythmicity, and some maintained rhythmicity but with altered expression patterns. Genes related to neuronal function, including those involved in protein homeostasis regulation, neuroinflammation, and ion homeostasis, showed significant changes in circadian rhythm amplitude and phase, and some completely lost their rhythmicity. These findings point to the following critical early events in Alzheimer’s disease: hippocampal circadian gene disruption occurs before cognitive symptoms emerge, genes related to neuronal function are uniquely susceptible to this early dysregulation, and circadian dysfunction may even precede the pathological changes of Alzheimer’s disease and influence disease onset. This work advances Alzheimer’s disease research by clarifying that circadian disruption is an early pre-symptomatic event, reinforcing the potential of circadian rhythm regulation as a strategy for early intervention of Alzheimer’s disease, and identifying neuronal pathways that may serve as intervention targets.  Related Articles | Metrics

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Astrocytes from P301S Tau mice exhibit non-canonical protein secretion and reduced morphological complexity Aishwarya G. Nadadhur, Matthew Mason, Johanna S. Rees, Marta Sidoryk-Wegrzynowicz, Aviva M. Tolkovsky, Maria Grazia Spillantini 2026, 21 (7):  3149-3155.  doi: 10.4103/NRR.NRR-D-24-01598 Abstract ( 75 )   PDF (5635KB) ( 16 )   Save Astrocytes have important neurosupportive functions in the brain that are altered in neurodegenerative diseases by unresolved mechanisms. We showed previously that astrocytes cultured from mice transgenic for human P301S-tau (P301S-mice) recapitulate the deficit in production and secretion of thrombospondin1 found in symptomatic P301S mouse brains, causing both reduced synapse formation and survival of cultured neurons. To further characterize how P301S-derived astrocytes differ from controls, we have compared the astrocyte-conditioned media of cultured astrocytes from postnatal day 7/8 P301S mice (P301S-astrocyte-conditioned media) versus controls (C57-astrocyte-conditioned media) using label-free liquid chromatography-mass spectrometry. We verified that thrombospondin1 secretion was significantly reduced in the P301S-astrocyte-conditioned media versus C57-astrocyte-conditioned media, demonstrating the robustness of the analysis. The most notable distinction was that ~57% of the P301S-astrocyte-conditioned media-enriched proteins were cytoplasmic proteins linked to cellular metabolism that are not predicted to be secreted via classical or non-classical secretion pathways, whereas ~88% of C57-astrocyte-conditioned media-enriched proteins comprised classically secreted proteins enriched in extracellular matrix components. These differences are associated with the finding that P301S-derived cultured astrocytes were smaller and in vivo appeared less mature in the cortex of P301S mice. The unconventional secretion pathway that P301S-astrocyte-conditioned media display shares similarities with several amyloid-β-exposed astrocyte-conditioned media, indicating that stimuli induced by tau and amyloid-β may induce a common adverse response pathway. Altogether, members of this adverse pathway may serve as a potential set of biomarkers to aid the clinical diagnosis of Alzheimer’s disease and other tauopathies, while the list of reduced neurosupportive factors could indicate new approaches to enhance neuronal survival by factor supplementation in tauopathies. Related Articles | Metrics

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Retrograde axonal transport of autophagic vesicles and dynein-dynactin protein interaction are attenuated during aging in the rat optic nerve in vivo Xiaoyue Luo, Jiong Zhang, Johan Tolö, Sebastian Kügler, Uwe Michel, Mathias Bähr, Jan Christoph Koch 2026, 21 (7):  3163-3170.  doi: 10.4103/NRR.NRR-D-24-01326 Abstract ( 85 )   PDF (1713KB) ( 15 )   Save Aging is characterized by a decreased autophagic activity contributing to the intracellular deposition of damaged organelles and macromolecules. Autophagy is particularly challenging in neurons since autophagic vesicles are formed at the axonal tip and must be transported to the soma where final degradation occurs. Here, we examined if axonal transport of autophagic vesicles is altered during aging. We employed two-photon microscopy for in vivo imaging in the optic nerve of young and aged rats. In old animals (> 18 months old), retrograde autophagic vesicle transport was significantly reduced with regard to motility and velocity. While activation of autophagy was decreased, expression of key proteins of the autophagy-lysosomal pathway including p62 and procathepsin D and the number of autophagolysosomes was increased. Maturation of autophagic vesicles was shifted to more distal regions of the axon and axonal lysosomal clearing was impaired. In a pull-down assay, the protein binding between dynein and dynactin was decreased by half, which could explain the retrograde axonal transport effects. Taken together, retrograde axonal autophagic vesicle transport in vivo is diminished during aging accompanied by decreased autophagy activation, alterations of the lysosomal pathway, and a reduced dynein-dynactin binding. Related Articles | Metrics

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Impairment of hippocampal long-term potentiation by soluble amyloid-β oligomers is mediated by glutamate transporter 1 expressed in neurons Shaomin Li, Jianlin Wang , Qianqin Guo , Yunxin Bai , Wen Liu , Kevin J. Hodgetts , Paul A. Rosenberg , Dennis J. Selkoe 2026, 21 (7):  3171-3177.  doi: 10.4103/NRR.NRR-D-24-00882 Abstract ( 155 )   PDF (2550KB) ( 8 )   Save In Alzheimer’s disease, perturbations of glutamate neurotransmission lead to synaptic dysfunction and synapse loss. Several studies have used glutamate transport inhibitors to demonstrate that soluble oligomers of amyloid-β induce synaptic dysfunction by interrupting glutamate uptake mediated by glutamate transporter 1, the major glutamate transporter in the brain. The cellular targets of the synaptic effects of soluble amyloid-β oligomers, including the nature of any interaction with glutamate transporter 1, remain ill-defined. We have generated a conditional glutamate transporter 1 knockout mouse to investigate celltype specific functions of glutamate transporter 1. Field excitatory postsynaptic potentials were examined in the CA1 region of mouse hippocampal slices. We confirmed that hippocampal long-term potentiation impairment is induced by both soluble Aβ oligomers and glutamate uptake inhibitors. Amyloid-β oligomers, including those isolated directly from the cortex of patients with Alzheimer’s disease, failed to inhibit hippocampal long-term potentiation in neuronal glutamate transporter 1 but not astrocytic glutamate transporter 1 knockout mice. The masking or occlusion of the effect of soluble Aβ oligomers by knockout of glutamate transporter 1 in neurons suggests that the metabolic or signaling consequences of knockout of glutamate transporter 1 in neurons and oAβ inhibition of synaptic plasticity show epistasis and thus share a similar molecular pathway. To extend these observations, we tested the effects of other types of manipulation of glutamate homeostasis on synaptic plasticity and the pathophysiology of soluble Aβ oligomers. Ceftriaxone, which upregulates glutamate transporter 1 levels, among other effects, prevented the impairment of long-term potentiation by soluble Aβ oligomers. Collectively, our findings suggest that the effects of amyloid-β on synaptic function are highly dependent on glutamate reuptake homeostasis and that the disruption of synaptic function by soluble Aβ oligomers is mediated by pathways linked to neuronal, not astrocytic, glutamate transporter 1. This study’s findings highlight the translational potential of targeting neuronal glutamate transporter 1 to counteract amyloid-β-induced synaptic dysfunction in Alzheimer’s disease. By showing that glutamate transporter 1 upregulation (e.g., via ceftriaxone) can prevent Aβ-related impairments, this research supports developing therapies aimed at modulating glutamate homeostasis to preserve synaptic function and combat cognitive decline in patients with Alzheimer’s disease. Related Articles | Metrics

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Bone marrow mesenchymal stem cells protect against cerebral amyloid angiopathy by enhancing neutrophil mitocytosis  Mengyan Hu, Haoton Yi, Shisi Wang, Xinmei Kang, Yuxin Liu, Zhiruo Liu, Huipeng Huang, Qin Qin, Liling Yuan, Wei Cai, Wei Qiu, Zhengqi Lu, Sanxin Liu 2026, 21 (7):  3178-3186.  doi: 10.4103/NRR.NRR-D-24-01273 Abstract ( 74 )   PDF (5435KB) ( 9 )   Save Current treatments for cerebral amyloid angiopathy are mainly symptomatic and have limited efficacy, and there is a lack of targeted therapies. Mesenchymal stem cell transplantation improves cognitive and motor function in conditions such as Alzheimer’s disease, acute ischemic stroke, and Parkinson’s disease. In addition, mesenchymal stem cell therapy modulates the immune system, reduces neuroinflammation, and improves resolution of brain lesions by cells of the macrophage lineage. Cerebral amyloid angiopathy and Alzheimer’s disease share similar pathologic changes involving amyloid-beta deposition, which contributes to the progression of both diseases and exacerbates cognitive deficits through impaired vascular integrity and neuroinflammation. Therefore, we hypothesized that mesenchymal stem cell therapy could also ameliorate the pathological changes seen in cerebral amyloid angiopathy by modulating the immune response. In this study, we show that bone marrow mesenchymal stem cells have a protective effect in a mouse model of cerebral amyloid angiopathy (Tg-SwDI/B). Bone marrow mesenchymal stem cell treatment improved cognitive function, reduced neuroinflammation, and maintained blood–brain barrier integrity in Tg-SwDI/B mice. Mechanistically, bone marrow mesenchymal stem cell treatment enhanced the expulsion of damaged mitochondria from neutrophils via migrasomes, in a process known as mitocytosis, thereby preserving mitochondrial quality within the neutrophils. Mitochondrial damage in neutrophils leads to cellular injury, including the generation of reactive oxygen species and the formation of neutrophil extracellular traps. Neutrophils activate mitocytosis to promote mitochondrial renewal, which further enhances their own clearance by macrophage lineage cells. Our findings demonstrate that bone marrow mesenchymal stem cells are a promising therapeutic candidate for cerebral amyloid angiopathy, as they play a significant role in migrasome-dependent mitochondrial quality control in neutrophils. Related Articles | Metrics

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Successful polyethylene glycol fusion repair using stored viable peripheral nerve allografts in Sprague–Dawley and Lewis rats Liwen Zhou, Cathy Z. Yang, Alexander M. Schafer, Alexa N. Olivarez, Arjun Agarwal, Guhan Periyasamy, Karthik Venkudusamy, Yessenia Montoya, Varun Gokhale, Rhea Sood, Henry Garcia, Jared S. Bushman, George D. Bittner 2026, 21 (7):  3187-3193.  doi: 10.4103/NRR.NRR-D-24-01505 Abstract ( 66 )   PDF (12450KB) ( 7 )   Save We have previously shown the success of polyethylene glycol fusion repair of segmental-loss peripheral nerve injuries in rats using freshly harvested, viable peripheral nerve allografts that can conduct action potentials. Because clinical application of polyethylene glycol fusion with viable peripheral nerve allografts demands pre-transplant donor tissue storage, we developed a protocol for ex vivo storage of rat sciatic nerves as viable peripheral nerve allografts, preserving many axons for up to 5 days. The current study evaluated the in vivo use of these stored viable peripheral nerve allografts. We hypothesized that stored viable peripheral nerve allografts with viable axons would enable successful in vivo repair of segmental-loss peripheral nerve injuries via polyethylene glycol-fusion. Polyethylene glycol-fused viable peripheral nerve allografts were classified as successful if they produced significantly improved locomotor recovery, as evaluated by the sciatic functional index, within 8 weeks post-repair. Many Sprague–Dawley and Lewis rats with successfully polyethylene glycol-fused viable peripheral nerve allografts had significantly improved sciatic functional index scores beginning at 5 weeks post-operatively. There was no significant difference in the efficiency and extent of successful polyethylene glycol fusion between stored and freshly harvested viable peripheral nerve allografts. In contrast, rats with non-fused negative control viable peripheral nerve allografts showed no recovery by 8 weeks post-operatively. Additional confirmatory outcome measures included in vivo compound action potentials and assessments of axon morphometry. These results suggest that viable peripheral nerve allografts can be stored and later used for successful polyethylene glycol fusion repair of segmental-loss peripheral nerve injuries. Related Articles | Metrics

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Identification of a natively resilient but poorly regenerating retinal ganglion cell type in the G protein-coupled receptor 88-Cre transgenic mouse Allison L. Hall, Christopher Zhao, Sean McCracken, Minglei Zhao, Zelun Wang, Andrea Santeford, Rajendra S. Apte, Philip R. Williams 2026, 21 (7):  3194-3201.  doi: 10.4103/NRR.NRR-D-24-01270 Abstract ( 93 )   PDF (8400KB) ( 12 )   Save Retinal ganglion cells are susceptible to neurodegenerative conditions and their death drives common forms of irreversible vision loss. In mice, there are 46 transcriptionally unique retinal ganglion cell types that demonstrate different susceptibilities to degeneration. Recent transcriptional experiments defined a novel retinal ganglion cell type that survives particularly well and uniquely expresses high levels of the orphan G-protein-coupled receptor 88. Motivated to study this retinal ganglion cell type, we obtained GPR88-Cre transgenic mice to identify the novel well-surviving retinal ganglion cells and examine their survival and regenerative potential. Our experiments demonstrate that this unidentified retinal ganglion cell type is likely accordant with previously described ON-direction-selective retinal ganglion cells. Interestingly, we find that ON-direction-selective retinal ganglion cells are resilient, but demonstrate limited potential to regenerate their axons in response to well-characterized regenerative treatments. Studying the molecular properties of the ON-direction-selective retinal ganglion cells could unlock new therapeutics to preserve retinal ganglion cells in patients. Related Articles | Metrics

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Lycium barbarum glycopeptide and luteolin synergistically protect mouse photoreceptors against N-nitroso-N-methylurea-induced degeneration Xiu Han, Qihang Kong, Yajing Liu, Xuesong Mi, Shibo Tang, Kwok-Fai So, Ying Xu 2026, 21 (7):  3202-3208.  doi: 10.4103/NRR.NRR-D-24-01473 Abstract ( 88 )   PDF (2875KB) ( 17 )   Save Photoreceptor degeneration is a major cause of vision impairment in retinal diseases, for which no effective treatment currently exists. Previous research by our team demonstrated that Lycium barbarum glycopeptide and luteolin can independently promote photoreceptor survival and function in degenerated mouse retinas, although with limited efficacy. This study evaluated whether a combination of Lycium barbarum glycopeptide and luteolin provides enhanced therapeutic benefits compared with either compound alone. Wild-type mice received a daily oral gavage of Lycium barbarum glycopeptide and luteolin for 7 days prior to intraperitoneal injection of N-nitroso-N-methylurea to induce photoreceptor damage. The treatment continued for an additional week after injury. Retinal structure and function were subsequently assessed using electroretinogram recordings, visual behavior testing, and immunostaining. Western blot analysis was conducted to investigate the underlying protective mechanisms. The results showed that the Lycium barbarum glycopeptide-luteolin mixture significantly increased photoreceptor survival, improved retinal light response, and enhanced visual behavior. Importantly, the combination outperformed either compound alone in protective efficacy. Mechanistic analysis indicated that the mixture suppressed retinal inflammation and modulated the extracellular signal-regulated kinase and Bcl-2-associated X protein/B-cell lymphoma 2 signaling pathways. These findings suggest that the combination of Lycium barbarum glycopeptide and luteolin represents a promising therapeutic strategy for photoreceptor degeneration. Related Articles | Metrics

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Decoding monocyte signatures in ischemic stroke: A multi-scale transcriptomic approach Yanyi Peng, Bo Xiao, Mengqi Zhang 2026, 21 (7):  3209-3224.  doi: 10.4103/NRR.NRR-D-24-01669 Abstract ( 71 )   PDF (22145KB) ( 6 )   Save Monocytes play a crucial role in post-stroke immune infiltration, yet the intricate immune regulatory networks they orchestrate in ischemic stroke remain poorly understood. This knowledge gap has hindered the development of targeted monocyte-based therapies for stroke. Here, we used a multi-omics approach combining single-cell and bulk transcriptomics. CellChat analysis revealed intercellular communication networks, while key genes were identified and predictive models built through Lasso regression. Immune cell infiltration dynamics were quantified using single-sample gene set enrichment analysis. Gene set enrichment analysis and gene set variation analysis identified disease-regulated pathways of core genes. MicroRNA networks and transcription factors were investigated using mircode and RcisTarget. Experimental validation was performed using oxygen–glucose deprivation and transient middle cerebral artery occlusion models, focusing on the influence of abhydrolase domain-containing protein 2 on monocyte function. We observed significantly elevated monocyte content in stroke brain tissue samples, and identified key monocyte genes associated with immune inflammation, chemokine signaling, and cell receptor function. A robust seven-gene predictive model for ischemic stroke was developed. CD274 strongly correlated with these seven genes, suggesting a potential immunomodulatory axis. In vivo transient middle cerebral artery occlusion experiments validated the predictive value of key genes. In vitro studies demonstrated that abhydrolase domain-containing protein 2 overexpression enhanced monocyte proliferation and phagocytic activity post-oxygen–glucose deprivation while reducing reactive oxygen species generation. In conclusion, this study maps post-stroke monocyte communication networks, identifies key signaling pathways, identifies regulatory mechanisms, and validates the functional importance of key genes, particularly abhydrolase domain-containing protein 2. These findings provide a foundation for developing targeted immunomodulatory therapies and precision diagnostics in ischemic stroke management. Related Articles | Metrics

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Hspb1 inhibits microglial ferroptosis and pro-inflammatory activation to alleviate cerebral ischemia/reperfusion injury in mice Weilong Hua, Hongye Xu, Rundong, Chen Yiyong Zeng, Lei Zhang, Yongxin Zhang, Xiaoxi Zhang, Yongwei Zhang, Hongjian Zhang, Jianmin Liu, Pengfei Yang 2026, 21 (7):  3225-3237.  doi: 10.4103/NRR.NRR-D-24-01532 Abstract ( 81 )   PDF (34158KB) ( 9 )   Save Investigating the mechanisms underlying central nervous system disorders is a major scientific issue in the 21st century. However, the inaccessibility and complexity of the human brain have always represented a challenge in understanding the pathophysiology of the central nervous system. Brain organoids are self-assembled three-dimensional aggregates derived from pluripotent stem cells with cell types and structures similar to the embryonic human brain, giving them potential for investigating the atypical cellular, molecular, and genetic characteristics characteristic of central nervous system disorders. Brain organoids also provide a platform for drug screening and serve as a potential source for transplantation therapy for brain injuries. However, the broad application of brain organoids is hampered by several limitations, such as the lack of high-fidelity cell types, insufficient maturation, and considerable heterogeneity, undermining their reliability in specific applications. This review summarizes brain organoid evolution, discusses recent technological and methodological innovations, and reviews their applications in drug screening, transplantation therapy, and disease modeling, as well as clinical research progress. Additionally, we emphasize the limitations of current brain organoid research and explore the potential for advancing the technology to enhance its applicability. Related Articles | Metrics

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Long-term real-world PM2.5 exposure induces depression-like behaviors in mice by disrupting nuclear factor erythroid 2-related factor 2-mediated astrocyte-to-microglia communication  Nannan Huang, Weiqing Shi, Cuishuang Dong, Bin Li, Yaohan Wang, Hanqing Chen, Xiaobo Li 2026, 21 (7):  3238-3248.  doi: 10.4103/NRR.NRR-D-24-01469 Abstract ( 84 )   PDF (9481KB) ( 7 )   Save Long-term exposure to ambient fine particulate matter (PM2.5) may increase the risk of neurotoxicity in human populations. However, research studies on the underlying mechanisms of chronic PM2.5-induced depression-like behaviors, and potential therapeutical strategies, remain scarce. In the present study, after long-term exposure to real-world PM2.5 for 15 weeks, male mice displayed depression-like behaviors, which were revealed using the open field and sucrose preference tests. Mechanistically, chronic PM2.5 exposure promoted astrocytic A1 polarization and disrupted reduction–oxidation balance in the mouse hippocampus. Furthermore, PM2.5-exposed mice displayed pathological damage to hippocampal neurons as well as the inhibition of nuclear factor erythroid 2-related factor 2 signaling. Astrocytic ablation of nuclear factor erythroid 2-related factor 2 exacerbated PM2.5-induced hippocampal neuronal injury in mice via the disruption of astrocyte-to-microglia communication; this finding was confirmed in mice with bilateral and unilateral hippocampal astrocytic Nfe2l2 knockdown. Importantly, the upregulation of nuclear factor erythroid 2-related factor 2 activation by procyanidin significantly ameliorated PM2.5-induced depression-like behaviors through the remodeling of astrocyte-to-microglia communication. Together, our findings shed light on the important role of hippocampal astrocytic nuclear factor erythroid 2-related factor 2 activation for maintaining astrocyte-to-microglia communication, and indicate potential research avenues for therapeutic strategies against PM2.5-induced depresson-like behaviors.  Related Articles | Metrics

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Integrative bulk and single-cell transcriptome analyses reveal RNA modification–related biomarkers of spinal cord injury Shixue Huang, Kun Jiao, Keqing Li, Jiayan Yuan, Haoming Shu, Yinuo Zhang, Xin Zhou, Xuhui Zhou 2026, 21 (7):  3249-3266.  doi: 10.4103/NRR.NRR-D-25-00080 Abstract ( 83 )   PDF (30862KB) ( 19 )   Save Aberrant RNA modification has been linked to the pathogenesis of various diseases; however, its specific molecular mechanisms in spinal cord injury remain poorly understood. The objective of this study was to explore RNA modification–related biomarkers of spinal cord injury. The mRNA expression profiles of mice with spinal cord injury were retrieved from the Gene Expression Omnibus (GEO) database (GSE18179). We identified 185 differentially expressed genes using bioinformatics approaches. Functional enrichment analysis demonstrated aberrant activation or inhibition of common metabolism–related pathways, including sulfur metabolism and steroid biosynthesis, in mice with spinal cord injury. An integrated strategy comprising weighted gene co-expression network analysis, a random forest model, a support vector machine model, and a generalized linear model was employed to identify four genes whose aberrant RNA modification was linked to spinal cord injury: Elovl6, Idi1, Sqle, and Stbd1. We verified the expression levels and diagnostic performance of these four genes in the original training dataset and mouse samples via receiver operating characteristic curve analysis. Quantitative reverse transcription-polymerase chain reaction demonstrated variations in the mRNA levels of the four genes between the Sham and spinal cord injury groups at different time points following injury. We also constructed microRNA–mRNA and transcription factor–mRNA interaction networks using Cytoscape. Additionally, we evaluated the proportions of 22 types of immune cells in the spinal cords of mice using the CIBERSORT tool, revealing significant alterations in the numbers of memory B cells, resting dendritic cells, M0 macrophages, activated mast cells, resting mast cells, and CD8+ T cells in spinal cord injury mice compared with Sham controls. Microglia and T cells were identified as key cell types by single-cell sequencing analysis. These findings provide new directions for the development of RNA modification–related therapeutic strategies for spinal cord injury and suggest that Elovl6, Idi1, Sqle, and Stbd1 are potential biomarkers of spinal cord injury.  Related Articles | Metrics

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Interferon regulatory factor 1 enhances T cell differentiation in myasthenia gravis Yuebei Luo, Yijun Ren, Zeyi Wen, Zhaohui Luo, Huan Yang, Liqun Xu 2026, 21 (7):  3267-3280.  doi: 10.4103/NRR.NRR-D-24-01646 Abstract ( 69 )   PDF (17369KB) ( 8 )   Save Interferon regulatory factor 1 is involved in many autoimmune conditions and is increased in patients with myasthenia gravis. However, its function in myasthenia gravis remains unclear. Herein, we explored the function of interferon regulatory factor 1 in myasthenia gravis, with an aim to understand the underlying mechanisms. Patients with myasthenia gravis who had acetylcholine receptor antibodies were included in the study. Peripheral blood lymphocytes were extracted from the included patients, and B lymphocyte subsets were isolated. Next, T and B cells from peripheral blood were co-cultured to explore the interferon regulatory factor 1-related mechanisms in myasthenia gravis. Chromatin immunoprecipitation experiments confirmed an interaction between interferon regulatory factor 1 and the CD180 promoter region. Dual-luciferase reporter gene confirmed the transcriptional activity of interferon regulatory factor 1 on CD180 promoter. In vitro results further indicated that interferon regulatory factor 1 promoted B cell activation and T cell differentiation via the inhibition of CD180. Interferon regulatory factor 1 recruited histone deacetylase 1 to inhibit CD180 transcription. Additionally, histone deacetylase 1 promoted B cell activation and T cell differentiation. Finally, in vitro experiments demonstrated that CD180 inhibited B cell activation and T cell differentiation by inhibiting the Toll-like receptor 4/mitogen-activated protein kinases/nuclear factor-kappa B pathway. Collectively, our results suggest that interferon regulatory factor 1 enhances T cell differentiation by recruiting histone deacetylase 1 to block B cell CD180 transcription in myasthenia gravis via the Toll-like receptor 4/mitogen-activated protein kinases/nuclear factor-kappa B pathway. Together, these findings indicate the important role of interferon regulatory factor 1 in myasthenia gravis and suggest its molecular mechanisms. They also provide new ideas and targets for diagnosing and treating myasthenia gravis, which will be both scientifically and clinically valuable.  Related Articles | Metrics