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    15 September 2026, Volume 21 Issue 9 Previous Issue    Next Issue
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    Technical system of electroencephalography-based brain–computer interface: Advances, applications, and challenges
    Hui Yu, Qiyue Mu, Chong Liu, Shuo Wang, Jinglai Sun
    2026, 21 (9):  3885-3907.  doi: 10.4103/NRR.NRR-D-25-00217
    Abstract ( 79 )   PDF (20936KB) ( 23 )   Save

    Electroencephalography-based brain–computer interfaces have revolutionized the integration of neural signals with technological systems, offering transformative solutions across neuroscience, biomedical engineering, and clinical practice. This review systematically analyzes advancements in electroencephalography-based brain–computer interface architectures, emphasizing four pillars, namely signal acquisition, paradigm design, decoding algorithms, and diverse applications. The aim is to bridge the gap between technology and application and guide future research. In signal acquisition, noninvasive systems using wet, dry, and semi-dry electrodes are more comfortable and gentler on the skin compared to traditional methods. However, ensuring stable signal quality over long periods of time remains a challenge. Minimally invasive approaches, such as microneedle arrays and endovascular probes, achieve near-invasive signal fidelity without major surgery. Paradigm design explores task-specific neural encoders. Although motor imagery paradigms are widely used in rehabilitation, they require weeks of user training. Steady-state visually evoked potential and P300 speller paradigms enable rapid calibration, but cause visual and cognitive fatigue. Advanced systems currently combine electroencephalography with electromyography or eye-tracking to better handle real-world tasks. Decoding algorithms have advanced through Riemannian geometry for improved noise filtering, deep learning architectures for automated spatiotemporal feature extraction, and transfer learning frameworks to minimize cross-subject calibration. However, challenges remain in managing inconsistent electroencephalography, reducing processing demands, and ensuring compatibility across different electroencephalography devices. Clinical trials reveal a predominant focus on stroke rehabilitation, while emerging frontiers include astronaut neuro-monitoring in space exploration. Challenges include improving signal accuracy, minimizing movement interference, addressing ethical data concerns, and ensuring real-world use. Future advancements focus on biocompatible nanomaterials, adaptive algorithms, and multimodal integration, positioning electroencephalography-based brain–computer interfaces as pivotal tools in next-generation neurotechnology.

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    Immune dysregulation and gut microbiota: Connection to health and disease development
    Ana Paula de Araújo Boleti, Pedro Henrique de Oliveira Cardoso, Breno Emanuel Farias Frihling, Luiz Filipe Ramalho Nunes de Moraes, Ellynes Amancio Correia Nunes, Lincoln Takashi Hota Mukoyama, Maria Eduarda Freitas Biembengute, Vívia Cleisla Bezerra de Melo, Marcos Fernandes Morales, Alinne Pereira de Castro, Ludovico Migliolo
    2026, 21 (9):  3906-3918.  doi: 10.4103/NRR.NRR-D-25-00244
    Abstract ( 42 )   PDF (2422KB) ( 8 )   Save
    Neuroinflammation is a key pathophysiological mechanism in various neurological diseases, such as Alzheimer’s disease and neuropsychiatric disorders. This review article analyzes the role of inflammatory mediators and their signaling pathways in the pathogenesis of neurodegenerative diseases, focusing on the molecular mechanisms that promote neurodegeneration and hinder neural regeneration. Recent evidence suggests that alterations in inflammatory processes in the brain are associated with cognitive impairment, progressive neurodegeneration, and impaired synaptic plasticity. Activation of Toll-like receptors triggers an inflammatory cascade involving proinflammatory cytokines such as interleukins and tumor necrosis factor alpha, which significantly contributes to neuronal dysfunction and cell death. Furthermore, we are investigating how these neuroinflammatory processes interfere with neural regeneration mechanisms and the maintenance of central nervous system homeostasis. Neural biomarkers associated with inflammation are emerging as potential diagnostic tools and therapeutic targets for neurological diseases, particularly anxiety disorders and Alzheimer’s disease. Both experimental and clinical studies suggest that interventions aimed at modulating neuroinflammation could be a promising therapeutic approach to promoting neuroprotection and stimulating neural regeneration. This review summarizes the latest research on the molecular mechanisms of neuroinflammation and its effect on brain function. It also highlights potential neuroprotective and regenerative strategies for treating neurological diseases.
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    Interaction of artificial intelligence, mental disorders, and diverse data modalities: Potential treatment management based on the “method–disease–data” axis
    Xu Tian, Ning Wang, Jin Yan, Yiming Chen, Ke Ma
    2026, 21 (9):  3919-3932.  doi: 10.4103/NRR.NRR-D-25-00121
    Abstract ( 64 )   PDF (14361KB) ( 2 )   Save

    Although many previous studies have highlighted the advances in prediction models, instruments for pathological and histological diagnosis and treatment, as well as individualized treatment modalities in mental disorders, these previous syntheses usually study the research outcomes separately and ignore the holistic integration of research regarding artificial intelligence technological approaches, data sets used and applications in mental health research. We used the BioBERT pretrained language model to systematically extract relevant information and develop an extensive knowledge graph that includes 3158 entities connected with 3248 different relationships. Our knowledge graph delineates essential artificial intelligence technological frameworks and explicitly maps out the relationships linking artificial intelligence methods, mental disorders, and diverse data modalities. The synthesis, centered on the analytical axis of “method-disease-data,” highlights key research areas where artificial intelligence and neuropsychiatry meet. Specifically, it focuses on key applications in early detection, improved accuracy of diagnosis, and individualized therapeutic interventions. In addition, we summarized the applications derived from basic research findings that extend to ongoing clinical trials, revealing the path toward future clinical application in psychiatric work. Importantly, the research paid special attention to the application of artificial intelligence in identifying key brain regions and neural circuits, providing important clues for elucidating the neural mechanisms of mental disorders and developing targeted interventions. Although artificial intelligence presents great opportunities, there are also significant challenges, including imbalanced data sets, ethical issues, and clinical concerns about trustworthiness and transparency. Strategies to address these challenges are proposed, and a perspective on emerging methods enabled by artificial intelligence is provided, which are expected to greatly change the management and treatment of the future.

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    Magnesium and nerve injury: Mechanisms and applications
    Hongye Yan, Su Pan, Longchuan Zhu, Weijian Kong, Zhiping Qi
    2026, 21 (9):  3933-3942.  doi: 10.4103/NRR.NRR-D-25-00263
    Abstract ( 31 )   PDF (3527KB) ( 2 )   Save
    Magnesium is a vital mineral that plays an important role in recovery from nerve injury recovery by inhibiting excitotoxicity, suppressing inflammatory effects, reducing oxidative stress, and protecting mitochondria. The role of magnesium ions in the field of nerve injury repair has garnered substantial attention. This paper aims to review the mechanisms of action and potential applications of magnesium in nerve injury repair. Magnesium ions, as key neuroregulatory factors, substantially alleviate secondary damage after nerve injury by inhibiting N-methyl-D-aspartate receptors, regulating calcium ion balance, providing anti-inflammatory and antioxidant effects, and protecting mitochondrial function. Magnesium ions have been shown to reduce neuronal death caused by excitotoxicity, inhibit the release of inflammatory factors, and improve mitochondrial function. Additionally, magnesium materials, such as metallic magnesium, magnesium alloys, surface-modified magnesium materials, and magnesium-based metallic glass, exhibit unique advantages in nerve repair. For example, magnesium materials can control the release of magnesium ions, thereby promoting axonal regeneration and providing mechanism support. However, the rapid corrosion of magnesium materials and the limited amount of research on these materials hinder their widespread application. Existing small-sample clinical studies have indicated that magnesium formulations show some efficacy in conditions such as migraines, Alzheimer’s disease, and traumatic brain injury, offering a new perspective for the application of magnesium in nerve injury rehabilitation. Magnesium ions and their derived materials collectively hold great promise for applications in nerve injury repair. Future efforts should focus on indepth research on the mechanisms of action of magnesium ions and the development of magnesium-based biomaterials with enhanced performance. Additionally, large-scale clinical trials should be conducted to validate their safety and efficacy.
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    Repairing spinal cord injuries: The most promising polymeric biomaterials and local drug delivery
    Inês Martins, Cláudia Nunes, Diogo Trigo
    2026, 21 (9):  3943-3951.  doi: 10.4103/NRR.NRR-D-25-00460
    Abstract ( 31 )   PDF (790KB) ( 4 )   Save
    Spinal cord injury results in severe sensory and motor deficits, with a dramatic impact on lifespan and healthspan, due to the limited regenerative capacity of the central nervous system. Following the initial injury, glial scarring and extracellular matrix barriers prevent axonal regeneration, while secondary damage exacerbates inflammation and tissue loss. The gold standard treatment in the last decades is acute surgery and systemic drug administration. New technologies have been developed, such as stem cell therapies, or the combinatory use of biomaterials, nonetheless still offering limited recovery. Successful therapies must act directly on neurons, activating regenerative pathways, while simultaneously promoting a pro-regenerative environment. However, polymeric materials have, in recent years, shown a regenerative potential through a series of different processes, from promoting neural regeneration by supporting tissue repair and reducing inflammation, to local drug delivery mechanisms. In this work, we systematize the state-of-the-art, exploring recent advancements in polymer-based therapies for spinal cord injury, discussing their characteristics, limitations, and promising future applications.
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    Artificial intelligence and peripheral neuropathies: Strategies for the development, application, and repair of regenerative biomaterials
    Zixu Zhang, Yi Yao, Zitao Wang, Huiyuan Bai, Maorong Jiang, Min Cai, Dengbing Yao
    2026, 21 (9):  3952-3963.  doi: 10.4103/NRR.NRR-D-25-00561
    Abstract ( 46 )   PDF (5701KB) ( 10 )   Save
    Traditional repair methods for peripheral neuropathies, such as autologous and allogeneic nerve grafts, face limitations, while peripheral nerve regeneration materials have emerged as a promising alternative. However, current biomaterials are mostly single-functional and insufficient in modulating the regenerative microenvironment. This review explores the application of artificial intelligence in the development of neural regenerative biomaterials, focusing on material design, performance prediction, and virtual experiments. Artificial intelligence has the potential to optimize material properties through machine learning and deep learning, predict material performance, and enhance nerve regeneration. Recent studies have demonstrated the ability of artificial intelligence to design biomaterials with improved biocompatibility and mechanical properties, as well as to accurately predict outcomes of nerve regeneration. However, several challenges remain, such as data integration, algorithm complexity, and ensuring clinical translation. The promising future of intelligent research and development in biomaterials lies in personalized treatment strategies, coupled with the integration of advanced technologies such as artificial intelligence and 3D bioprinting, to create more efficient neural repair materials. This review highlights the transformative potential of artificial intelligence in advancing peripheral nerve repair and improving patient outcomes. 
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    When copper turns killer: Decoding copper dyshomeostasis and cuproptosis in neurodegenerative pathogenesis and precision metal interventions
    Wei Du, Tingyao Wu, Yonggang Fan, Min Zhao
    2026, 21 (9):  3964-3976.  doi: 10.4103/NRR.NRR-D-25-00808
    Abstract ( 76 )   PDF (10872KB) ( 7 )   Save
    Copper is an essential cofactor for neuronal metabolism, enzymatic functions, and neurotransmission. However, copper dyshomeostasis-induced redox activity makes the brain vulnerable to oxidative and proteostatic stress. Cuproptosis, a recently characterized form of programmed cell death, is triggered by copper binding to lipoylated enzymes of the tricarboxylic acid cycle, resulting in proteotoxic stress, mitochondrial dysfunction, and cell death. Given that mitochondria are central to copper handling and the primary site of cuproptosis, we examine mitochondrial pathways and key cuproptosis-related genes. We also assess disease-specific signatures of copper imbalance. In Alzheimer’s disease, excess copper binds to amyloid-β, promoting aggregation and neurotoxicity. In Parkinson’s disease, copper-bound α-synuclein fosters aggregation, while copper-driven redox cycling elevates reactive oxygen species. Cuproptosis worsens mitochondrial vulnerability in Parkinson’s disease and impairs cellular stress responses in Huntington’s disease. In amyotrophic lateral sclerosis, superoxide dismutase 1-related defects compromise antioxidant defenses alongside copper-dependent mitochondrial dysfunction. In prion diseases, copper facilitates prion protein misfolding and toxicity. Across these disorders, common features include mitochondrial dysfunction and cuproptosis hallmarks—such as enhanced protein lipoylation, elevated reactive oxygen species, impaired electron transport chain activity, fragile Fe–S clusters, and increased reliance on the tricarboxylic acid cycle—which collectively increase neuronal susceptibility to copper dyshomeostasis. Clarifying and understanding the critical roles of copper metabolism not only elucidates the pathogenesis of neurodegenerative diseases but also offers alternative therapeutic strategies. This review uniquely integrates the mitochondria-centered cuproptosis axis with copper dyshomeostasis across Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and prion diseases, mapping convergent vulnerabilities to mechanism-grounded interventions and outlining testable translational routes.
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    Myelin, white matter, and social deficits in autism spectrum disorder
    Omri Kimchi-Feldhorn, Ariel Nir Sade, Boaz Barak
    2026, 21 (9):  3977-3982.  doi: 10.4103/NRR.NRR-D-25-00366
    Abstract ( 37 )   PDF (1180KB) ( 4 )   Save
    Autism spectrum disorder is a neurodevelopmental disorder characterized by social interaction challenges, restricted and repetitive behaviors or interests, and communication difficulties. Emerging evidence suggests that disruptions in myelin, the fatty substance that insulates nerve fibers, may play a significant role in shaping the behavioral characteristics observed in individuals with autism spectrum disorder, particularly those related to social behavior. This article provides an overview of current understanding of the interplay between white matter and myelin deficits, social behavior, and autism spectrum disorder. As such, it aims to deepen our understanding of the underlying mechanisms of autism spectrum disorder and potentially contribute to the development of more targeted interventions and support strategies for individuals affected by the disorder.
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    Interspecies differences in the expression of cannabinoid receptors at the tissue and cellular level
    Sydney Lawley, Audrey Green, Cole Johnson, Michael D. Burton
    2026, 21 (9):  3983-3990.  doi: 10.4103/NRR.NRR-D-25-00806
    Abstract ( 46 )   PDF (7064KB) ( 5 )   Save
    Understanding the cellular and molecular distribution of cannabinoids can address a highly contentious perspective in the pain neuroscience field: whether cannabinoids are viable in pain relief. Due to insufficient evidence for cannabinoids in reducing pain in clinical trials and gaps in knowledge across the translational research process, the International Association for the Study of Pain (IASP) published a position statement in 2021 recommending against the general use of cannabinoids to treat pain. A possible mechanistic reason for the lack of translatability is interspecies differences in the expression of the cannabinoid type 1 and type 2 receptors at the tissue and cellular levels. Additionally, the anatomical site that is most important for analgesia has been elusive. This review aims to provide a deeper understanding of the anatomical distribution of cannabinoid receptors throughout the nervous system across species. We traverse historical and contemporary literature to illustrate the progression of methodology and perspectives. We discuss co-localized markers on cannabinoid receptor-expressing cells to elucidate possible anatomically dependent roles of the endocannabinoid system. We also discuss differences in cannabinoid receptor expression across species that may contribute to challenges in translatability between rodents and humans. Lastly, we cover how various types of pain can differentially alter the expression of cannabinoid receptors and how this may impact cannabinoid-based therapeutics.
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    Lights for ageing: can photobiomodulation restore functionality in the cerebral networks of aged individuals?
    Marjorie Dole, John Mitrofanis
    2026, 21 (9):  3991-3996.  doi: 10.4103/NRR.NRR-D-25-00633
    Abstract ( 55 )   PDF (2877KB) ( 6 )   Save
    Of all our organs, the brain is particularly prone to aging. The neurons become increasingly more dysfunctional with age, leading to less efficient patterns of functional connectivity, not only within, but also between the different large-scale resting-state networks. Further, the aged brain shows weaker, less efficient patterns of activation when undertaking a particular task, such as a motor movement or recalling a memory. Quite remarkably, however, compensatory mechanisms do develop, where other brain regions are recruited to help perform the tasks. There is, however, much variability across different individuals in the ability to recruit such compensatory processes, and this has been referred to as cognitive reserve or resilience. In addition to these neuronal dysfunctions, the aged brain suffers from widespread inflammation. In terms of options to slow the aging process, there is nothing specific on offer, except for some recommendations to live a healthier life (e.g., change in diet, more exercise, and cognitive training). In this narrative review, we explore the idea that the use of red and near infrared light, referred to often as photobiomodulation, can slow neuronal wear and tear, reduce inflammation, enhance the overall function of the cerebral networks, and improve the quality of life in aged individuals. We hypothesize that the application of these specific wavelengths of light has the potential to improve aged-induced cell dysfunction and death, leading to a restoration of more functional patterns of activity across the aged brain and reducing the risk of developing a neurological disorder such as stroke or neurodegenerative disease.
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    Restoration of gamma-aminobutyric acid homeostasis: A novel approach to alleviating central nervous system injury–associated immunodepression syndrome
    Ping Yang, Di Tian, Zijiao Li, Zhongxiang Yao
    2026, 21 (9):  3997-4011.  doi: 10.4103/NRR.NRR-D-25-00147
    Abstract ( 43 )   PDF (2720KB) ( 4 )   Save
    Injuries to the central nervous system can disrupt body functions and often cause excessive sympathetic activity, leading to immune suppression known as central nervous system injury–associated immunodepression syndrome. The connection between central nervous system injury and central nervous system injury–associated immunodepression syndrome is not fully clear. Gamma-aminobutyric acid, an important inhibitory neurotransmitter, helps excitation-inhibition balance in the nervous system, especially after spinal cord injuries. Impaired gamma-aminobutyric acid signaling causes an excitation-inhibition imbalance, which worsens neural plasticity, increases sympathetic overactivity, and may lead to central nervous system injury–associated immunodepression syndrome. This review discusses the roles of gamma-aminobutyric acid in protecting central nervous system structure and function and how its dysfunction contributes to abnormal plasticity and heightened reflexes. We also explore new treatments aimed at restoring gamma-aminobutyric acid balance, such as modulating potassium-chloride cotransporter 2, enhancing activity-dependent recovery, targeting microglial responses, and dietary approaches. Maintaining healthy gamma-aminobutyric acid activity is essential for preventing immune issues following central nervous system injury. This review emphasizes the regulation of gamma-aminobutyric acid as a promising target for future treatments of central nervous system injury-associated immunodepression syndrome. 
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    Nose–brain axis: A bridge from the nasal cavity to the central nervous system
    Guohui Yang, Dongdong Zhu, Kaizhi Zhang
    2026, 21 (9):  4012-4019.  doi: 10.4103/NRR.NRR-D-25-01770
    Abstract ( 52 )   PDF (2496KB) ( 16 )   Save
    The nose–brain axis is a direct pathway linking the nasal cavity to the central nervous system. Odors, as well as exogenous substances such as pathogens, inflammatory mediators, and drugs, can enter the cranial cavity through pathways including the olfactory nerve, trigeminal nerve, and humoral routes, thereby enabling signal transmission and material exchange from the peripheral nasal cavity to the central nervous system. In recent years, advances in multimodal visualization technologies have made it possible to dynamically monitor the nose–brain axis from the molecular level to the tissue level, providing important means for revealing its functional characteristics and pathological changes. Owing to the existence of the nose–brain axis, nasal inflammation can, through neuro-immune interactions, activate central microglia and astrocytes and induce neuroinflammation, thus promoting the onset and progression of central nervous system diseases. In addition, the nose–brain axis offers a unique route for the treatment of central nervous system disorders. Intranasal drug delivery can bypass the blood–brain barrier, act directly on the central nervous system, increase intracranial drug bioavailability, and produce rapid effects, providing new ideas for treating cross-system diseases. This review systematically summarizes the anatomical pathways of the nose–brain axis, visualization monitoring technologies, and mechanisms by which nasal inflammation affects the central nervous system. It also reviews advances in intranasal drug delivery for emotional disorders, migraine, Parkinson’s disease, and Alzheimer’s disease, aiming to provide new strategies for studying the mechanisms by which nasal inflammation influences the central nervous system and for cross-system targeted therapy.
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     Long non-coding RNAs: Emerging regulators of diverse programmed cell death pathways in neurons
    Noah C. Mathew, Kevin K. Park
    2026, 21 (9):  4020-4027.  doi: 10.4103/NRR.NRR-D-25-00233
    Abstract ( 76 )   PDF (2700KB) ( 8 )   Save
    Long non-coding RNAs have emerged as pivotal regulators of diverse biological processes, particularly in the modulation of regulated neuronal cell death pathways. This review highlights the roles of long non-coding RNAs in programmed neuronal cell death, focusing on apoptosis, necroptosis, ferroptosis, and pyroptosis. Dysregulation of these processes contributes to neurodegenerative disorders and neurological injuries, emphasizing the importance of understanding how long non-coding RNAs influence these pathways. Apoptosis, essential for neuronal development, can lead to pathology when misregulated. Necroptosis, a caspase-independent inflammatory process, involves the modulation of necrosome components. Pyroptosis, mediated by inflammasomes, affects inflammasome assembly and cytokine release. Ferroptosis, driven by iron accumulation and lipid peroxidation, is influenced by changes in antioxidant defenses. By detailing the roles of long non-coding RNAs in these mechanisms, this review underscores their therapeutic potential for mitigating neuronal loss.
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    cGAS–STING pathway modulation: A new hope for neural regeneration
    Jinghan Zhang, Mouyuan Sun, Yaxian Luo, Mikko Petteri Räisänen, Lianjie Peng, Luying Qin, Mengfei Yu, Haifei Shi
    2026, 21 (9):  4028-4044.  doi: 10.4103/NRR.NRR-D-24-01516
    Abstract ( 44 )   PDF (28531KB) ( 8 )   Save
    In recent decades, the limitations of therapeutic interventions have elevated neurological disorders and injuries to a prominent position in academic research. Existing neurotherapeutic methodologies have demonstrated insufficient efficacy in fostering neural regeneration. The current integration of precision medicine technologies and innovative tissue engineering methods holds significant promise for attaining neural regeneration. The cGAS–STING pathway, a pivotal component of the innate immune system, plays a crucial role in the pathological processes of various neurological diseases and injuries. In neuroinflammatory diseases and neural injuries, aberrant activation of the cGAS–STING pathway amplifies neuroinflammation, type I interferon responses, and cell death. Inhibition of cGAS–STING-related genes holds promise for promoting neural regeneration following disease recovery and defect regeneration. In this review, the foundational pathophysiological mechanisms underlying cGAS–STING-related gene regulation in neurological disorders and injuries are elucidated with a special emphasis on its implications in nerve-related cells. In this review, we highlight the advances in tissue engineering technologies that integrate cGAS–STING pathway modulators, highlighting their potential therapeutic efficacy in modulating neural regeneration. Nevertheless, the role of the cGAS–STING pathway in neural regeneration remains relatively limited. Bibliometric analysis demonstrates a significant correlation of cGAS–STING pathway activation with various neuropathological processes. Studies have progressively focused on the critical role of this pathway in neurological diseases and injuries. As it stands, the effectiveness of tissue engineering technologies involving cGAS–STING-related gene modulators in achieving neural regeneration remains unfulfilled in its potential. Future research must apply advanced omics technologies to further delineate the exact functions of the cGAS–STING pathway in neural regeneration. Integration of these results with precision medicine approaches will be necessary for creating tissue engineering biomaterials with capabilities for precise delivery and targeted controlled release of cGAS–STING-related genes in neural regeneration-related cells, towards functional recovery from neurological injury and diseases.
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    Thalamic reticular nucleus in the pathophysiology of schizophrenia
    Gonzalo Flores, David J. Apam-Castillejos, Hannaford Edwards, Victor M. Magdaleno-Madrigal, Juan Nacher, Hiram Tendilla-Beltrán, Lalit K. Srivastava
    2026, 21 (9):  4045-4050.  doi: 10.4103/NRR.NRR-D-25-00928
    Abstract ( 35 )   PDF (2506KB) ( 7 )   Save
    Mechanistic analyses on schizophrenia have traditionally focused on corticolimbic structures such as the prefrontal cortex, hippocampus, and amygdala, given their established roles in cognition. However, the thalamus, a critical hub that interconnects these regions, has garnered comparatively less attention. Of particular interest is the thalamic reticular nucleus, which plays a crucial role in cognition and sensory processing through its connections with the dorsomedial thalamic nucleus and the prefrontal cortex. A potential role of the thalamic reticular nucleus in schizophrenia has been suggested in a few reports; however, recent analyses have identified a specific link between the thalamic reticular nucleus and layer 5 neurons of the prefrontal cortex, a relationship highlighted by our group’s earlier findings from 2012, which demonstrated that bilateral thalamic reticular nucleus lesions in adult rats caused neuronal atrophy in these cortical neurons. Building on this foundation, this manuscript explores the role of the thalamic reticular nucleus in schizophrenia neurobiology by reviewing its functional neuroanatomy, its integration within the corticolimbic system, and mechanisms of its potential involvement in the disease. This hypothesis is further developed by describing our novel findings from rats with neonatal ventral hippocampus lesion, widely considered a developmental model for schizophrenia. For the first time, we report dendritic spine pathology in thalamic reticular nucleus neurons, characterized by reduced spine density and a lower proportion of mushroom spines. Furthermore, we demonstrate a decrease in the density of parvalbumin-positive cells within the thalamic reticular nucleus in the neonatal ventral hippocampus lesion model. Together, these findings suggest significant alterations in the corticolimbic network and position the thalamic reticular nucleus as a complex yet promising mechanistic contributor to the neurobiology of schizophrenia.
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    Multi-omics technologies: Novel tools and methods for assessing nerve injury and regeneration
    Qiang Zhou, Zongren Zhao, Da Tan, Chenhao Fang, Zhaoli Shen, Shun Li, Xianzhen Chen
    2026, 21 (9):  4051-4060.  doi: 10.4103/NRR.NRR-D-25-00610
    Abstract ( 59 )   PDF (11073KB) ( 1 )   Save
    Recently, with the rapid advancement of multi-omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, new tools and approaches have been introduced for studying nerve injury and regeneration. This review highlights the application and progress of multi-omics in uncovering the mechanisms of nerve injury, guiding the development of regenerative strategies, and promoting clinical translation. By integrating multi-omics datasets, researchers can comprehensively track dynamic molecular changes following nerve injury, including abnormal gene expression, disrupted protein signaling, altered metabolic programs, and shifts in the immune microenvironment. Single-cell multi-omics technologies resolve cellular heterogeneity, revealing the distinct functions of neurons, glial cells, and immune cell subpopulations during the injury response. Spatially resolved transcriptomics maintain the spatial context of lesion and regeneration sites, enabling precise localization for targeted interventions. Multi-omics technologies not only identify key molecular players involved in nerve regeneration but also create opportunities for personalized medicine. Nonetheless, integrating multi-omics data poses technical challenges, including high dimensionality, batch effects, and algorithmic constraints, while ethical concerns related to stem cell therapy and gene editing require stringent oversight. To transition from structural reconstruction to functional remodeling, future research should emphasize artificial intelligence–driven data integration, organ-on-a-chip modeling, and cross-disciplinary collaboration to overcome existing technical barriers and accelerate the clinical application of neuroregenerative therapies. 
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    Hypoxia-inducible factor-1: A new neuroprotective agent for the treatment of hyperglycemia after stroke
    María Isabel Hernández, José L. Zugaza, Abraham Martín
    2026, 21 (9):  4061-4067.  doi: 10.4103/NRR.NRR-D-25-00794
    Abstract ( 40 )   PDF (4695KB) ( 4 )   Save
    Acute hyperglycemia in ischemic stroke occurs in almost half of cases, inducing a worsening of the underlying pathophysiology. Hence, the management of acute hyperglycemia during the first hours following ischemic stroke requires well-defined strategies. Furthermore, the effect of hyperglycemia on stroke remains an unresolved paradoxical process whose possible causes are still unknown. The ischemic process involves the activation of multiple signaling pathways related to cell death and survival, which can be acutely altered by hyperglycemia, causing subsequent worsening of the ischemic process. In search of potential biological targets to combat this medical burden, the role of hypoxia-inducible factor appears as a novel neuroprotective agent that needs further investigation. Furthermore, hypoxia-inducible factor protein targets multiple pathways changing depending on factors such as the severity of hypoxia, the time elapsed after reperfusion and the specific cell type. In fact, the poor prognosis of ischemic stroke associated with acute hyperglycemia has been linked to alterations in hypoxia-inducible factor-1α protein function. Together, these findings support this transcription factor as a new therapeutic target to prevent the negative effect of hyperglycemia, opening new avenues for treatment in stroke.
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    Roles of spinal V3 interneurons: Roles in controlling movement in healthy and injured conditions
    Ruoying Zhang, Wei Wang, Xiaolong Zheng
    2026, 21 (9):  4068-4075.  doi: 10.4103/NRR.NRR-D-25-00191
    Abstract ( 65 )   PDF (2243KB) ( 1 )   Save

    Spinal V3 interneurons are glutamatergic neurons that are distributed among the dorsal, intermediate, and ventral spinal cord. They are involved in broad neural circuit connections in the central nervous system. Functionally, they play important roles in locomotion, such as the maintenance of robust and balanced gaits during walking. More importantly, after spinal cord injury, these neurons maintain their excitability and facilitate proprioceptive sensory transmission to motor neurons, which are crucial for the initiation of complex coordinated reciprocal and rhythmic activities that resemble locomotion. Thus, spinal V3 interneurons appear to be good candidates for the restoration of locomotion after spinal cord injury. Nevertheless, therapeutic strategies targeting spinal V3 interneurons for spinal cord injury are scarce. In this review, we summarize the functional roles of spinal V3 interneurons in locomotion across uninjured and injured states and come up with possible strategies targeting them to restore locomotor function after spinal cord injury. Currently, an increasing number of studies are dedicated to identifying spinal V3 interneurons and their roles in motor, sensory, and autonomic nervous system functions. However, there are still many unclear questions regarding the molecular and functional characteristics of V3 interneurons in the spinal cord, as well as their potential therapeutic effects after spinal cord injury. Future research should prioritize the in-depth characterization of this specific neuronal subpopulation based on its sensorimotor features to further enhance spinal cord repair and functional recovery.

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    Prostaglandins: Key players in immunomodulation of the nervous system
    Ziqin Wang, Ying Sun, Minjie Luo, Nina He, Zhongchi Wen, Zuzhen Wang, Yonglong Zhang, Jie Zhao, Ying Liu
    2026, 21 (9):  4076-4088.  doi: 10.4103/NRR.NRR-D-25-00089
    Abstract ( 58 )   PDF (5843KB) ( 3 )   Save

    As a class of bioactive substances that play important roles in a variety of physiological and pathological processes, prostaglandins have attracted increasing research attention. Published studies have identified the molecular characteristics of prostaglandins in peripheral organs, the enzymes involved in prostaglandin biosynthesis, and prostaglandin receptors. Some studies have also explored the characteristics of prostaglandins and their functions in the central nervous system. In particular, for immunomodulation, prostaglandins in the brain show a unique immunosuppressive effect, which is of great importance for maintaining brain immune homeostasis and preventing excessive immune responses. In this review, we review the biosynthesis and degradation of prostaglandins, discuss the regulatory effects of prostaglandin systems on the immune cells of the nervous system, and explore the therapeutic potential of targeting prostaglandin systems for neurological diseases, thereby providing new perspectives for the treatment of these diseases. Overall, prostaglandins play important roles in the immunomodulation of the nervous system, and the complexity of the underlying processes depends on the variety and types of specific receptors and, more importantly, the cell types prostaglandins act on. Therefore, additional in-depth studies of the specific mechanisms involving prostaglandins in immunomodulation, including the interactions among different types of prostaglandins and their roles in neuropathological conditions, are essential. The prostaglandin signaling pathway may represent another important direction for the development of new drugs for neurological diseases, and the combination of prostaglandin system targets with other therapies (such as immunomodulatory drugs and gene therapy) may yield better results.

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    Reactive aldehyde species-mediated neuropathic pain in spinal cord injury: Mechanisms and therapeutic opportunities
    Rachel L. Stingel, Nicholas S. Race, Riyi Shi
    2026, 21 (9):  4089-4099.  doi: 10.4103/NRR.NRR-D-25-00126
    Abstract ( 35 )   PDF (4851KB) ( 5 )   Save
    Spinal cord injury–related neuropathic pain is difficult to treat and significantly decreases quality of life. Often functionally limiting and refractory to conventional pharmacologic treatments, treating spinal cord injury–related neuropathic pain necessitates the exploration of novel mechanistic therapeutic strategies. Mounting preclinical and clinical evidence suggests that neurotoxic reactive aldehyde species such as acrolein, produced endogenously in high concentrations following spinal cord injury, are putative therapeutic targets in spinal cord injury–related neuropathic pain. The purpose of this review is to synthesize the current knowledge of mechanisms underlying reactive aldehyde species–mediated pain following spinal cord injury and propose novel drug strategies for future investigation. In doing so, we aim to highlight emerging evidence that supports the use of interventions designed to decrease reactive aldehyde species and their potential to mitigate the detrimental impacts of neuropathic pain in spinal cord injury. Ultimately, reactive aldehyde species–targeted therapeutics may have implications beyond spinal cord injury, as reactive aldehyde species play a pivotal role in the pathology of many neurological disorders.
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    A new paradigm of bidirectional regulation of the gut– spinal cord axis
    Songzhi Ni, Kai Chen, Haojue Wang, Shenyuan Chen, Yuanyu Qiu, Tianjiao Wang, Fengfeng Mo, Shige Wang, Bo Li, Yushu Bai, Jiulong Zhao, Xiao Zhai, Zhaoshen Li
    2026, 21 (9):  4100-4111.  doi: 10.4103/NRR.NRR-D-25-01016
    Abstract ( 68 )   PDF (4891KB) ( 9 )   Save
    The bidirectional interactions of spinal cord injury, multiple sclerosis, and amyotrophic lateral sclerosis with the gut operate through a distinct gut–spinal cord axis, rather than being fully explained by the conventional gut–brain axis. The spinal cord, with its unique anatomical and physiological features, serves as a central hub of communication. The gut and spinal cord communicate through various pathways, including the immune system and the autonomic and enteric nervous systems. This review summarizes existing clinical and basic research on the relationship between gut homeostasis and spinal cord diseases. First, we present findings from epidemiological studies showing that patients with spinal cord disorders often exhibit altered gut function, which may be influenced by antibiotic exposure and environmental factors. Second, we review the key physiological and anatomical structures of the gut-spinal cord axis, including the intestinal barrier, gut microbiota, and enteric nervous system, all of which are involved in maintaining gut health, as well as sensory neurons, motor neurons, and interneurons in spinal nerve regulation. Third, we describe the roles of the three axes (microbial, immune, and neural) in bidirectional regulation and their pathological mechanisms. Moreover, vicious cycles involving these axes can exacerbate spinal cord disorders. Fourth, we outline potential biomarkers in the gut–spinal cord axis, such as uridine, hypoxanthine, and 5-methoxytryptophan. Fifth, we propose several treatment strategies with potential clinical applications, including fecal microbiota transplantation and the use of probiotics and prebiotics. Finally, this review emphasizes the gut–spinal cord axis as a promising therapeutic target, highlighting the need for multi-omics integration, longitudinal cohort studies, and individualized interventions to resolve existing debates. Overall, the recognition of the gut–spinal cord axis provides a conceptual shift that extends beyond the gut–brain framework.
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    Mitochondrial DNA homeostasis: A novel therapeutic target for neurodegenerative diseases
    Tingting Fu, Xinyi Chen, Shuting Zhang, Ying Fu, Ling Huang, Wandi Xiong
    2026, 21 (9):  4112-4121.  doi: 10.4103/NRR.NRR-D-25-00495
    Abstract ( 44 )   PDF (3209KB) ( 4 )   Save
    The mitochondrial genomic homeostasis is essential for the function of the oxidative phosphorylation system and cellular homeostasis. Mitochondrial DNA is particularly susceptible to aging-related oxidative stress due to the lack of a histone coat. Disturbances in mitochondrial DNA may contribute to functional decline during the aging process and in neurodegenerative diseases, leading to further impairment of mitochondrial DNA and initiating a vicious cycle. To date, it remains unclear how disturbed mitochondrial DNA is involved in the etiology of pathological aging and neurodegenerative diseases. The purpose of this review is to clarify the crucial roles of mitochondrial DNA homeostasis in the pathogenesis of neurodegenerative diseases. Mitochondrial DNA is distributed within nucleoids and is then transcribed into polycistronic mitochondrial DNA molecules within the mitochondrial granule region. Within the ultrastructure of the mitochondrial nucleoid and granule, a group of essential mitochondrial proteins involved in DNA replication, DNA transcription, RNA translation, RNA surveillance, and RNA degradation plays a crucial role in maintaining mitochondrial structure, genome integrity, and mitochondrial DNA processing. The uniparentally inherited mitochondrial DNA undergoes heritable polyploid variations, which include homoplasmy and heteroplasmy. Accumulating mitochondrial DNA alterations, such as deletions, point mutations, and methylations, occur during the pathogenic processes of neurodegenerative diseases. The increased mitochondrial DNA alterations can be propagated by the rise of deleterious heteroplasmy in neurodegenerative diseases, ultimately resulting in impairment to the oxidative phosphorylation system, biogenesis defects, and cellular metabolic dysfunction. Therefore, developing appropriate gene editing tools to rectify aberrant alterations in mitochondrial DNA and targeting the key proteins involved in maintaining mitochondrial DNA homeostasis can be considered promising therapeutic strategies for neurodegenerative diseases. Although therapeutic strategies targeting mitochondrial DNA in diseases show great potential, challenges related to efficacy and safety require a better understanding of the mechanisms underlying mitochondrial DNA alterations in aging and neurodegenerative diseases. 
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    Microbiota–gut-brain axis and bile acids–driven neuromodulation
    Taiwei Dong, Tianyi Zhang, Huanhuan Wang, Jing Zhang, Reema Abdullah, Binggui Sun, Guoping Peng
    2026, 21 (9):  4122-4134.  doi: 10.4103/NRR.NRR-D-25-00927
    Abstract ( 64 )   PDF (5059KB) ( 6 )   Save

    Bile acids emerge as multifunctional signaling molecules with dual hepatic and microbial origins, acting through farnesoid X receptor and Takeda G protein‑coupled receptor 5 to influence inflammation and metabolism. Their dysregulation is consistently observed across various neurodegenerative diseases. The microbiota–gut–brain axis is a pivotal conduit for bile acids-driven neuromodulation, while sex-specific bile acid profiles and signaling pathways introduce critical biological heterogeneity. Emerging translational evidence indicates the promise of bile acids as biomarkers and therapeutic targets, yet highlights the critical hurdles that need to be addressed to realize precision interventions. Our core findings are: (1) Bile acids are far more than mere metabolic byproducts. They orchestrate core pathological processes such as neuroinflammation and energy metabolism. Their functions, whether neuroprotective or neurotoxic, are highly context-dependent, varying with cell type and disease-specific pathological backgrounds, thus exhibiting a potent “double-edged sword” effect. (2) The “microbiota–bile acids–brain axis” serves as a crucial bridge linking peripheral metabolic dysregulation to central nervous system pathology. (3) Sexual dimorphism emerges as a fundamental biological variable essential for understanding the heterogeneity in bile acid profiles and disease susceptibility. The primary contribution of this work is the proposal of an integrated “microbiota-bile acids-sex” framework that systematically describes the key scientific challenge of the context-dependent, dual roles of bile acids. Ultimately, this review champions a paradigm shift from a traditional brain-centric view to a systemic, metabolic perspective, establishing the bile acid system as a promising target for future precision therapeutic interventions.

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    Deep learning–based cognitive impairment brain imaging analysis: New methods, new technologies, and new paradigms
    Qingqin Xu, Jianwei Lu, Zhongfu Zhang, Dongsheng Xu, Chengxiang Guo
    2026, 21 (9):  4135-4147.  doi: 10.4103/NRR.NRR-D-25-00332
    Abstract ( 71 )   PDF (17100KB) ( 1 )   Save
    Cognitive impairment arising from ischemic stroke, Alzheimer’s disease, and Parkinson’s disease presents distinct structural and network-level alterations. Brain magnetic resonance imaging offers a non-invasive and high-resolution approach to assess these changes, while deep learning provides powerful tools for automated analysis. Given that accurate lesion delineation, precise localization of abnormal regions, and reliable disease classification are fundamental to clinical decision-making. This review aims to explore the application of deep learning techniques to brain magnetic resonance imaging analysis of cognitive impairments caused by these disorders, with a focus on three core tasks: lesion segmentation, object detection, and image classification. Recent widely accepted findings indicate that ischemic stroke studies have achieved state-of-the-art lesion segmentation performance, with optimized U-shaped convolutional network (U-Net) and hybrid convolutional neural network-transformer models reaching Dice scores up to 0.911 in delineating focal damage. Alzheimer’s disease research has advanced classification and staging accuracy by more than 10% compared with unimodal baselines through three-dimensional convolutional neural network, Transformers, and multimodal fusion, enabling more precise detection of diffuse cortical atrophy. Parkinson’s disease imaging, despite lacking overt structural lesions, has leveraged ResNet and Vision Transformer backbones to identify subtle and spatially distributed abnormalities, improving early-stage differentiation. Persistent challenges include the scarcity of large, high-quality annotated datasets, substantial inter-site variability, high annotation costs, and limited interpretability, hindering clinical integration. Addressing these barriers will require advances in federated learning to mitigate data scarcity while preserving privacy, domain adaptation techniques to reduce inter-site variability, automated annotation, and low-resource training strategies to lower labeling costs, and explainable artificial intelligence to improve interpretability, thereby ensuring model robustness, privacy, and transparency. This review highlights emerging methods, innovative technologies, and novel paradigms that are redefining brain imaging analysis in cognitive impairment. Mechanistically, deep learning improves cognitive impairment analysis by integrating hierarchical and multiscale spatial features, modeling long-range functional connectivity disruptions, and fusing structural with functional imaging to better represent network-level pathology. In conclusion, aligning network architectures with disease-specific imaging characteristics and task requirements can greatly enhance the accuracy, robustness, and generalizability of magnetic resonance imaging analyses for cognitive impairment. Future work should focus on multimodal fusion, structure-function coupling, cross-disease evaluations, and embedding artificial intelligence tools into clinical workflows to support early detection, individualized treatment planning, and large-scale clinical adoption.
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    Role of voltage-dependent anion channel 1 in neurodegeneration: Mechanisms, implications, and therapeutic potential
    Astha Parikh, Anas Cholavaram, Ajith Kumar Chitti Babu, Kanagavel Deepankumar, Murali Vijayan
    2026, 21 (9):  4148-4156.  doi: 10.4103/NRR.NRR-D-25-00368
    Abstract ( 52 )   PDF (1172KB) ( 5 )   Save
    Voltage-dependent anion channel 1 is an integral outer membrane protein of the mitochondria that governs apoptosis, enables metabolite exchange, and influences mitochondrial activity. In neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease, oxidative stress, neuroinflammation, and mitochondrial dysfunction are frequent features. Voltage-dependent anion channel 1 is a key regulator of these processes. This review described the structure, membrane topology, and physiological function of voltage-dependent anion channel 1 in neurons and glial cells. We emphasize how it affects mitophagy, oxidative damage, and changes in mitochondrial permeability. Special attention is focused on how voltagedependent anion channel 1 interacts with pathogenic proteins that damage mitochondrial integrity and cause neurotoxicity, including mutant huntingtin, phosphorylated tau, α-synuclein, amyloid-beta, and TAR DNA-binding protein 43. Furthermore, the paper examines the function of voltage-dependent anion channel 1 in astrocytic dysfunction and microglial activation, highlighting its impact on neuroinflammation. In a nutshell, we assess treatment strategies that target voltage-dependent anion channel 1, such as VBIT-4, a selective inhibitor of voltagedependent anion channel 1 oligomerization, and newer methods, including structure-based drug design and CRISPR/Cas9 regulation. Improved knowledge of the hinter voltage-dependent anion channel 1 of the molecular mechanism may allow for new therapeutic approaches in neurodegenerative diseases.
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    Neuromodulation techniques targeting neurotransmitter dysfunction: Innovation in treatments for Alzheimer’s disease
    Siyuan Jin, Bingqi Guo, Wensi Hao, Xin Su, Tingting Zhang, Chunyan Liu
    2026, 21 (9):  4157-4168.  doi: 10.4103/NRR.NRR-D-25-00582
    Abstract ( 49 )   PDF (1370KB) ( 15 )   Save
    Alzheimer’s disease is a neurodegenerative disorder characterized by progressive cognitive decline, synaptic dysfunction, and neurotransmitter imbalance. Novel neuromodulation approaches, both non-invasive and invasive, show promising potential for restoring neural circuit integrity and improving cognition. This review aims to elucidate the relationship between neuromodulation, neural network circuits, and neurotransmitters. It systematically synthesizes recent advances in neuromodulation techniques, focusing on their ability to modulate four critical neurotransmitter systems: cholinergic, glutamatergic, GABAergic, and monoaminergic systems. Additionally, this review establishes a critical association between neurotransmitter regulation and synaptic plasticity mechanisms, proposing a novel “circuit-transmitter” triad framework for intervention. It represents the first systematic integration of the neurotransmitter regulation mechanisms of various neuromodulation techniques while evaluating their clinical viability for Alzheimer’s disease intervention. Beyond established targets, this review identifies the hippocampus-thalamus axis, linked via direct entorhinal-thalamic projections, as a promising focus for ultrasonic neuromodulation research. 
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    Thermal challenge and food intake: Mutual regulatory mechanisms 
    Alán Alpár
    2026, 21 (9):  4169-4176.  doi: 10.4103/NRR.NRR-D-25-00170
    Abstract ( 48 )   PDF (4711KB) ( 2 )   Save
    Human energy homeostasis principally depends on thermal and food intake regulation mechanisms. In addition to describing the major pathways, brain centers, and their connections which control these functions, this review focuses on (i) interrelations between thermoregulation and food intake, (ii) the role of tanycytes, and (iii) the regenerative capacity of the system in mammals. In the arcuate nucleus, anorexigenic proopiomelanocortin/melanocyte-stimulating hormone neurons and orexigenic neuropeptide Y/agouti-related peptide neurons are reached by a wealth of diet-induced (e.g., leptin, ghrelin, or insulin) or hormonal (e.g., thyroid hormone) signals. These neurons are not only sensitive to temperature signals but also point to both direct and indirect executors of thermoregulation through axonal projection onto the sympathetic system, by producing cleaved proopiomelanocortin products and by reaching endocrine orchestrators, including corticotropin-releasing hormone and thyrotropin-releasing hormone neurons in the paraventricular nucleus. Meanwhile, ambient temperature affects food intake: the warm-cold separated spinobrachial-preoptic area pathways ultimately target agouti-related peptide neurons to attenuate or increase cold-evoked feeding. The brainstem, hypothalamic, and preoptic area centers of these pathways are reached by a wide array of modulatory signals, which refine thermal and dietetic regulation according to conditions such as daily cycle, stress, or fever. We also review regulating mechanisms that are activated in an extreme form of fasting when food becomes unavailable: a specific body temperature control in hibernating animals during the winter months. Understanding this mechanism could likely contribute to medical applications; i.e., artificial induction of a hibernation-like hypometabolic state. Tanycytes uniquely shape energy homeostasis: they dynamically shape the blood–brain barrier to regulate neurohormone sequestration into the brain parenchyme, but also shuttle between the blood circulation and the cerebrospinal fluid bidirectionally. Therefore, blood- or liquorborne signals not only target arcuate hypothalamic neurons from different circulatory systems, but the activity of diverse groups of neurohormone (such as leptin or ghrelin)-sensitive periventricular neurons will be synchronized. Tanycytes can likely link thermal and food-intake regulations: they carry receptors (most importantly transient receptor potential cation channel subfamily V member 1, glucose, and cytokine receptors) which enable them to sensitively monitor and react to both thermal and energy homeostatic challenges, including anorexia, while they reduce feeding in heat exposure via a specific parabrachial-tanycyte-hypothalamic circuitry. Tanycytes also emerge as the source for the regenerative potential of thermal and energy homeostasis: they not only display functional and morphological plasticity but also neural stem cell properties; they supply the arcuate nucleus with new neurons in both temperature- and diet-responsive manners, which are compromised in extreme/pathological heat challenges or diet-induced obesity, respectively.
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    The potential and therapeutic advances of the integrin family in neurological disorders
    Xingfang Zhang, Liang Gao, Yiwen Wang, Qian Meng, Min Bai, Dong Xu, Yanhua Wang, Jianv Wang, Hongtao Bi, Yi Ding
    2026, 21 (9):  4177-4194.  doi: 10.4103/NRR.NRR-D-25-00020
    Abstract ( 55 )   PDF (27197KB) ( 11 )   Save
    Neurological disorders encompass a diverse and heterogeneous group of medical conditions, including cerebrovascular diseases (e.g., stroke), neurodegenerative diseases (e.g., Alzheimer’s disease and Parkinson’s disease), and autoimmune demyelinating disorders (e.g., multiple sclerosis). With the global aging population, the incidence of these disorders continues to rise, posing significant challenges to healthcare systems and socio-economic structures. Recent studies have highlighted integrins—a family of transmembrane glycoprotein receptors—as critical regulators of central nervous system function, making them a focal point in neurological disease research. By interacting with the extracellular matrix, integrins modulate cell adhesion, signal transduction, and inflammatory responses, playing indispensable roles in neuronal development, synaptic plasticity, and blood–brain barrier maintenance. Dysregulated integrin signaling has been implicated in the pathophysiology of various neurological disorders, suggesting that integrin-targeting interventions, including integrin antagonists or agonists, could represent novel therapeutic strategies. Preclinical and clinical studies have demonstrated that modulating integrin function influences disease progression, offering promising avenues for the development of precision medicine approaches. This review provides a comprehensive analysis of integrin structure, classification, and their physiological and pathological roles in the central nervous system, with a focus on their molecular mechanisms in neurological disorders. Furthermore, we evaluate the therapeutic potential and challenges associated with integrintargeted interventions. By elucidating the mechanistic underpinnings of integrin function in the central nervous system, this review aims to advance our understanding of their translational potential, laying the groundwork for the development of innovative therapeutic strategies.
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    M2 polarization of macrophages: Manipulation of spinal cord injury repair
    Yiran Lu, Hantian Yin, Lingwei Lou, Zhonglin Liu, Haiming Zhu, Chunyi Gu, Can Zhang, Junjuan Wang
    2026, 21 (9):  4195-4210.  doi: 10.4103/NRR.NRR-D-24-01579
    Abstract ( 62 )   PDF (4812KB) ( 3 )   Save
    Spinal cord injury results in lasting sensory and motor dysfunction with limited regenerative capacity. Macrophages play a crucial role in orchestrating secondary pathogenesis and repair mechanisms through polarization dynamics. Following spinal cord injury, these immune cells deploy context-dependent responses via divergent regulatory pathways, mediating phagocytic clearance, inflammatory modulation, and neural tissue remodeling. M1 macrophage polarization exacerbates tissue damage through cytokine storms, reactive oxygen species generation, and subsequent neuronal apoptosis, axonal fragmentation, and glial scarring. Conversely, dominant M2 polarization provides neuroprotection by resolving inflammation and promoting axonal sprouting. Strategic manipulation of macrophage plasticity is a promising frontier in spinal cord injury recovery therapy. This review comprehensively examines the regulatory mechanisms that govern macrophage polarization after spinal cord injury, the functional distinctions between resident microglia and peripheral macrophages, the pathophysiological cascades that occur across injury subtypes, and the emerging interventions that span nanotherapeutics, engineered exosomes, electroactive biomaterials, and photobiomodulation. However, there is still a lack of clinical therapies centered around macrophages due to a lack of human trials targeting macrophage reprogramming and excessive reliance on rodent models without validation in non-human primates. However, given the accelerated development of immunomodulatory biomaterials and the expanding mechanistic insights into polarization pathways, the precision targeting of macrophages warrants prioritized investigation for transformative spinal cord injury therapeutics.
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    Zinc homeostasis imbalance: Potential therapeutic value in neurodegenerative diseases
    Zheyi Zhang, Wei Deng, Leilai Hu, Yulong Hu, Shenglan Zhang, Yaping Xiong, Xiao Liu, Peng Yu, Shuchun Yu, Linhui Yuan Jing Zhang
    2026, 21 (9):  4211-4220.  doi: 10.4103/NRR.NRR-D-25-00632
    Abstract ( 79 )   PDF (3434KB) ( 5 )   Save
    Zinc homeostasis genes are a general term for a family of genes responsible for regulating the concentration of intracellular and extracellular zinc ions, including the SLC39 (ZIP) family, the SLC30 (ZnT) family, and the metallothionein family. As an essential trace element, zinc is involved in biomolecular synthesis, energy metabolism, redox regulation, and gene expression. Recent studies have shown that abnormal expression of zinc homeostasis genes mediates neuronal apoptosis through multiple pathways, including oxidative stress and neuroinflammation. Imbalance in zinc homeostasis can result in the pathological development of various neurodegenerative disorders, including the deposition of amyloid-β in Alzheimer’s disease and the aberrant aggregation of α-synuclein in Parkinson’s disease. Therefore, regulating the expression of zinc homeostasis genes to restore normal zinc levels in vivo may be an effective strategy for treating neurodegenerative diseases. This review comprehensively summarizes the current status of research exploring zinc homeostasis genes across various family subtypes, as well as the altered expression of these genes in different neurodegenerative diseases and the underlying mechanisms. Finally, we propose zinc chelator supplementation as a novel interventional therapy for neurodegenerative diseases. This proposal includes an evaluation of the feasibility, safety, and limitations of this treatment, providing an innovative perspective for the clinical management of neurodegenerative diseases in the future. 
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    Lifestyle risk factors of white matter brain aging: Evidence, potential mechanisms, and future direction
    Tianzhou Ma, Zhenyao Ye, Li Feng, Shuo Chen
    2026, 21 (9):  4221-4222.  doi: 10.4103/NRR.NRR-D-25-01039
    Abstract ( 34 )   PDF (748KB) ( 6 )   Save
    Population aging has greatly increased the global burden of neurodegenerative diseases. As we age, the structure and function of our brain undergo significant changes, including brain volume decline, cortical thinning, white matter deterioration, and altered functional connectivity, among others, resulting in cognitive decline and an elevated risk of neurodegenerative diseases. However, there is significant individual variation in how fast the brain ages and the timing of when these changes emerge and progress into age-related diseases. A previous study has used advanced machine learning (ML) methods to predict age from magnetic resonance imaging (MRI) data in healthy people (Franke and Gaser, 2019). Various risk factors, both modifiable and non-modifiable, were found to influence the brain aging process, either delaying or accelerating its progression (Cole, 2020).
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    Role of the subthalamic nucleus in motor control
    Gabriel González-Escamilla, Nils Schöter, Sergiu Groppa
    2026, 21 (9):  4223-4224.  doi: 10.4103/NRR.NRR-D-25-01197
    Abstract ( 37 )   PDF (4972KB) ( 4 )   Save
    Situated below the thalamus, the subthalamic nucleus (STN) functions as an excitatory relay within the indirect pathway, influencing both the suppression of involuntary movements and fine motor execution. While the STN has traditionally been associated with motor inhibition, emerging evidence highlights its complex connectivity with cortical, striatal, pallidal, and brainstem structures, enabling precise modulation of movement intensity, timing, and coordination.
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    T-cell immunoglobulin and mucindomain containing-3 orchestrates myeloid dysfunction across brain aging and disease
    Berta Segura-Collar, Lucia Mondejar-Ruescas, Carmen Jareño-Bonilla, Ricardo Gargini
    2026, 21 (9):  4225-4226.  doi: 10.4103/NRR.NRR-D-25-01348
    Abstract ( 37 )   PDF (6462KB) ( 3 )   Save
    The old definition of the central nervous system as an “immune privilege” site is now considered obsolete, as it has been demonstrated that there is a complex interaction between immune cells and other brain cells, which creates an environment-controlled surveillance with different immune niches that are now beginning to be understood. Thus, brain aging is characterized by a series of immunological, vascular, and metabolic changes that erode defense mechanisms and neuronal homeostasis of the neural circuits. Among the most notable is inflammaging, defined as a basal state of low-grade chronic inflammation that progressively sets in and affects synaptic function, neuronal plasticity, and cell viability. This proinflammatory environment is accompanied by dysregulation of resident immune cells, especially in microglia and brain macrophages, which progressively transition from a homeostatic phenotype to a regulatory-immunosuppressive state (Segura-Collar et al., 2025). The progressive loss of integrity of the blood-brain barrier is a key event in this process, as it allows the entry and persistence of peripheral immune cells with the ability to adapt to the brain microenvironment, thereby accelerating the onset and chronicity of neurodegenerative and neoplastic diseases (Segura-Collar et al., 2022).
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    Glial heterogeneity in the primate spinal cord: Implications of age and sex differences for neurodegenerative and neurotraumatic diseases
    Chloé M. Gazard, Gaëtan Poulen, Florence E. Perrin
    2026, 21 (9):  4227-4228.  doi: 10.4103/NRR.NRR-D-25-01274
    Abstract ( 38 )   PDF (1114KB) ( 4 )   Save
    The central nervous system (CNS) relies on the intricate interplay between neurons and glial cells to maintain homeostasis and coordinate responses to disease or injury. It is now well established that within this network, astrocytes, microglia, and oligodendrocytes are critical regulator of neural function, actively shaping metabolism, inflammation, and therefore degenerative and repair processes. Glial dysfunction and alteration of dynamic cross-communication among the glial cell population have emerged as a common denominator in both neurodegenerative and neurotraumatic conditions. It is therefore clear that glial cells are not passive bystanders but active contributors to CNS health and disease.
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    Glucagon-like peptide-1 receptor agonists to modulate neuroinflammation and neurogenesis
    Rosalie Elvira, Eng King Tan, Zhi Dong Zhou
    2026, 21 (9):  4229-4230.  doi: 10.4103/NRR.NRR-D-25-01144
    Abstract ( 52 )   PDF (2265KB) ( 5 )   Save
    Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally developed as drugs for type 2 diabetes and obesity, exhibit therapeutic effects for various neurological disorders recently, with multiple neuroprotective mechanisms. The GLP-1RAs therapy has been applied to acute ischemic stroke, where they limit neuroinflammation, stabilize the neurovascular unit, and reduce infarct volume. The GLP-1RAs drugs have also been tested for Wolfram syndrome, where they mitigate endoplasmic reticulum (ER) stress and inhibit neuronal apoptosis. Preclinical analyses demonstrate that GLP-1RAs can modulate neuroinflammation processes, including reprogramming of microglia towards antiinflammatory phenotypes, suppression of nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome activation, suppressing pathological astrogliosis, and rebalance of peripheral immunity. Furthermore, GLP-1RAs were identified to enhance synaptic plasticity, improve cognitive deficits, and promote hippocampal neurogenesis via regulation of brain-derived neurotrophic factor/cAMP response element-binding protein (BDNF/CREB) and insulin-like growth factor 1 (IGF-1) pathways. However, embedded multimodal biomarkers (e.g., TREM2, neuroimaging, and neurogenesis markers) are required for further clinical translation and clinical trial investigation of target engagement, dosage optimization, and patient stratification. Future prioritizing mechanism-focused studies in the niche will help unlock the potential of GLP-1RAs as disease-modifying therapies for human neurological disorders.
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    Role of angiogenic signaling through placental growth factor in white matter injury and cognitive decline
    Madhavi Akella, Parissa Irom, Kyle C. Kern, Jason D. Hinman
    2026, 21 (9):  4231-4232.  doi: 10.4103/NRR.NRR-D-25-00454
    Abstract ( 39 )   PDF (776KB) ( 7 )   Save
    Vascular contributions to cognitive impairment and dementia (VCID) remain a significant public health concern. Age-associated disruptions in cerebral blood flow and brain vascular permeability resulting from cerebral small vessel disease (CSVD) are the main drivers of VCID. There is a stark absence of pharmacological treatments specific to CSVD, in part due to challenges in diagnostic accuracy for CSVD pathology during the prodromal phase before clinical dementia. Magnetic resonance imaging (MRI) is the benchmark method for detecting cerebrovascular pathologies, which predominate in subcortical white matter regions. Advanced MRI techniques, including diffusion tensor imaging (DTI), which have higher diagnostic accuracy for prodromal CSVD are not routinely acquired in clinical scans. Highly sensitive and accurate blood-based biomarkers that inform the pathogenic cascades associated with CSVD and VCID offer a minimally invasive means of identifying individuals who are at risk for VCID.
     
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    Rab5 hyperactivation: The central hub for endolysosomal dysfunction in Down syndrome
    Xu-Qiao Chen
    2026, 21 (9):  4233-4234.  doi: 10.4103/NRR.NRR-D-25-00967
    Abstract ( 57 )   PDF (807KB) ( 2 )   Save
    Rab5 as a central regulator of the endolysosomal network: The endolysosomal network (ELN) comprises a dynamic system of membranebound organelles responsible for cargo trafficking, degradation, and intracellular signaling, all of which are essential for maintaining cellular homeostasis. Within this system, members of the Rab family of small GTPases serve as key regulators of vesicular transport, marking specific compartments. Among them, Rab5 plays a pivotal role in orchestrating the formation of the early endosome (EE), membrane fusion events, and the transition of EE to downstream stages. Like other Rab proteins, Rab5 cycles between an active GTP-bound state and an inactive GDPbound state. This cycle is tightly controlled by guanine nucleotide exchange factors, which activate Rab5 by facilitating GDP-GTP exchange, and GTPase-activating proteins, which inactivate it by promoting GTP hydrolysis.
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    Retinal tauopathy as a biological indicator of Alzheimer’s disease
    Bhakta Prasad Gaire, Yosef Koronyo, Keith L. Black, Dieu-Trang Fuchs, Maya Koronyo-Hamaoui
    2026, 21 (9):  4235-4236.  doi: 10.4103/NRR.NRR-D-25-01096
    Abstract ( 38 )   PDF (697KB) ( 8 )   Save
    The retina, a laminated neural tissue at the back of the eye, is increasingly recognized as a site of central nervous system pathology in Alzheimer’s disease (AD) (Gaire et al., 2024). Developmentally derived from the embryonic diencephalon, the retina maintains a direct anatomical and physiological connection to the brain, comprising neurons, glial populations, and vascular structures that closely resemble those in the cerebral cortex. Both retina and brain originate from the neural ectoderm during embryogenesis and exhibit a layered cytoarchitecture composed of specialized neurons, supportive glia (astrocytes and microglia), and tightly regulated vasculature. These structures are protected by analogous blood-tissue barriers, the blood-retinal and blood–brain barriers, which mediate selective permeability and immune responses. While the brain is enclosed by the opaque skull and requires sophisticated, often expensive neuroimaging modalities for visualization, the retina is uniquely accessible through the transparent ocular media. This enables direct, high-resolution, noninvasive imaging of neuronal, glial, vascular, and molecular features in vivo using relatively affordable and clinically available technologies, including optical coherence tomography, scanning laser ophthalmoscopy, and increasingly, adaptive optics, hyperspectral imaging, and machine learning-based analytic platforms.
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    Delta9-tetrahydrocannabinol: A blunt weapon or a doubleedged sword for virus-induced neuroinflammation
    Alison R. Van Zandt, Miranda D. Horn, Andrew G. MacLean
    2026, 21 (9):  4237-4238.  doi: 10.4103/NRR.NRR-D-25-01394
    Abstract ( 34 )   PDF (772KB) ( 2 )   Save
    Delta9-Tetrahydrocannabinol (Δ9-THC), the primary psychoactive component of cannabis, has demonstrated both neuroprotective and antiinflammatory properties, while also having the potential to impact the blood–brain barrier and cognitive function with chronic use. A previous study hosted at Tulane National Biomedical Research Center showed that chronic Δ9-THC administration prior to simian immunodeficiency virus (SIV) infection reduced viral load and generalized inflammation, including in the cerebellum (Molina et al., 2011). Although the effect of Δ9-THC on reducing microglial activation has been explored in the context of chronic human immunodeficiency virus (HIV) infection, the influence of Δ9-THC on the initial seeding of the central nervous system (CNS) reservoir, reservoir persistence, and downstream neurodegeneration remains largely unknown. This perspective explores the impact of cannabinoids on HIV neuropathology with a focus on regenerative potential.
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    Targeting the NLRP3–NEK7 axis with rebamipide: Drug repurposing in Parkinson’s disease
    Hye-Sun Lim, Gunhyuk Park
    2026, 21 (9):  4239-4240.  doi: 10.4103/NRR.NRR-D-25-01189
    Abstract ( 24 )   PDF (3105KB) ( 2 )   Save
    Introduction — from traditional wisdom to modern challenges: Drug repurposing has become a strategic pillar in pharmaceutical development, addressing the rising challenges of novel drug discovery (Saranraj and Kiran, 2025). The conventional pipeline is often arduous > $2 billion per approval, with < 10% clinical success. The burden is even heavier in programs in the central nervous system (CNS) due to the blood–brain barrier, disease heterogeneity, and limited biomarkers (Saranraj and Kiran, 2025). These inefficiencies create a bottleneck for neurodegenerative diseases, underscoring the need for faster, lower-risk strategies such as drug repurposing to deliver therapies more quickly.
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    Integration of functional magnetic resonance imaging and artificial intelligence in Alzheimer’s disease
    Liqin Yang, Yuxin Li, Kuangyu Shi, Axel Rominger, Ruiqing Ni
    2026, 21 (9):  4241-4242.  doi: 10.4103/NRR.NRR-D-25-01816
    Abstract ( 33 )   PDF (724KB) ( 17 )   Save
    Alzheimer’s disease (AD), the most common cause of dementia, is a progressive neurodegenerative disease characterized by progressive cognitive decline and memory loss. Mild cognitive impairment (MCI) is the prodromal stage of AD, with a conversion rate of 10%–15% per year and 50% conversion rate longitudinally. The pathological features of AD include the aberrant accumulation of amyloid-β plaques, neurofibrillary tangles formed by hyperphosphorylated tau and synaptic dysfunction (Nussbaumer et al., 2025), all of which have cascading effects on the brain activity of AD patients. Functional magnetic resonance imaging (fMRI), specifically blood oxygenation level–dependent fMRI, is a non-invasive and radiation-free technique for indirectly measuring brain activity. It should be noted that fMRI has a double-edged sword nature. While fMRI is a powerful tool for detecting whole-brain-wide alterations in neural activity, its high sensitivity to brain states and complex analysis methods and indices also result in poor reproducibility across studies and compromise its further application in clinical practice. The results derived from extremely limited unpaired samples (e.g., before and after treatment in the same patients) or a longitudinal study design should be further explored.
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    A metabolic perspective on microglia in Alzheimer’s disease
    Moris Sangineto, Gaetano Serviddio
    2026, 21 (9):  4243-4244.  doi: 10.4103/NRR.NRR-D-25-01035
    Abstract ( 26 )   PDF (6092KB) ( 3 )   Save
    Alzheimer’s disease (AD) is the most common form of dementia, with 50 million people affected worldwide in 2019. With the continuous ageing of populations, the number of AD cases is expected to rise to approximately 150 million by 2050 (Sangineto et al., 2023). Given its significant impact on healthcare systems and society, novel biomarkers and therapeutic approaches are urgently needed.
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    Remodeling of the glutamatergic system in the Alzheimer’s disease medial temporal lobe and superior temporal gyrus
    Marina Wasef, Andrea Kwakowsky
    2026, 21 (9):  4245-4246.  doi: 10.4103/NRR.NRR-D-25-01177
    Abstract ( 25 )   PDF (574KB) ( 4 )   Save
    Alzheimer ’s disease (AD) is a progressive neurodegenerative disease characterized by memory loss and cognitive decline. Beyond the accumulation of amyloid-beta (Aβ) plaques and tau neurofibrillary tangles, the hallmark pathologies of AD, glutamatergic dysregulation, and excitotoxicity are key contributors to disease progression. Given that glutamate is the main excitatory neurotransmitter and has a central role in the regulation of synaptic plasticity, memory, and learning, any disturbance in glutamate signaling can disrupt normal brain function. The medial temporal lobe and superior temporal gyrus (STG) are severely impacted in AD, and the remodeling of glutamate receptors and transporters has been extensively examined as mechanisms linked to neuronal network dysfunction.
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    Setting shapes the strain: Untangling alpha-synuclein heterogeneity
    James A. Wiseman, Kreesan Reddy, Glenda Halliday, Birger Victor Dieriks
    2026, 21 (9):  4247-4248.  doi: 10.4103/NRR.NRR-D-25-01287
    Abstract ( 26 )   PDF (1049KB) ( 12 )   Save
    The landscape of α-synucleinopathies is both clinically and pathologically diverse, encompassing Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and several less common nonclassical syndromes, including PLA2G6-associated neurodegeneration, POLG-associated neurodegeneration, Niemann-Pick type C1, and Krabbe disease. Although each disease is defined by α-synuclein (α-Syn) aggregation, the striking diversity in onset age, anatomical distribution, and clinical course demands an explanation beyond protein misfolding alone. We contend that the key to resolving this paradox is understanding how α-Syn aggregates and their surrounding biological microenvironments co-evolve to shape disease trajectories.
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    Passive immunotherapy for Parkinson’s disease in 2025: Status and perspective
    Alba González-Artero, Oriol Bárcenas, Jordi Pujols, Salvador Ventura
    2026, 21 (9):  4249-4250.  doi: 10.4103/NRR.NRR-D-25-01792
    Abstract ( 41 )   PDF (1984KB) ( 7 )   Save
    Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease (AD). As a multisystem disorder, it presents with a complex and heterogeneous clinical profile (Kalia and Lang, 2015). The hallmark motor symptoms include bradykinesia, resting tremor, muscular rigidity, and postural instability. In addition, PD encompasses a wide spectrum of nonmotor symptoms such as anosmia, rapid eye movement sleep behavior disorder, mood disturbances, and cognitive decline. As neurodegeneration progresses, patients experience a marked deterioration in quality of life, often resulting in long-term disability and a high degree of dependence on caregivers. Despite decades of research, available treatments for PD remain symptomatic, primarily aimed at restoring dopaminergic function or compensating for its loss. No disease-modifying therapies capable of halting or reversing neurodegeneration have yet been approved. This therapeutic gap has driven intensive efforts to develop novel strategies to block, slow, or reverse PD pathology. Among these, immunotherapeutic approaches have attracted increasing attention, inspired by recent advances in AD, with several monoclonal antibodies targeting amyloid-β now approved for clinical use.
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    Targeting the dopaminergic midbrain in Alzheimer’s disease: Therapeutic potential of focusing on specific neural circuits rather than single molecular pathways
    Emanuele Claudio Latagliata, Stefano Puglisi-Allegra, Marcello D’Amelio
    2026, 21 (9):  4251-4252.  doi: 10.4103/NRR.NRR-D-25-00925
    Abstract ( 56 )   PDF (639KB) ( 1 )   Save
    Alzheimer’s disease (AD) remains one of the most unyielding challenges in neurology. Its complexity and heterogeneity underscore a critical need to explore additional mechanisms that can be targeted in the early stages of the disease to prevent the worsening of functional decline.
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    Microglia in C9orf72–associated amyotrophic lateral sclerosis: More or less active?
    Björn F. Vahsen, R. Jeroen Pasterkamp
    2026, 21 (9):  4253-4254.  doi: 10.4103/NRR.NRR-D-25-01831
    Abstract ( 29 )   PDF (1693KB) ( 10 )   Save
    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron (MN) loss and muscle wasting, ultimately leading to death due to respiratory failure. A hexanucleotide (GGGGCC) repeat expansion (HRE) in C9orf72 is the most common genetic cause of ALS (C9-ALS) and frontotemporal dementia. C9orf72 HRE causes ALS through different mechanisms, which include reduced C9orf72 expression, the generation of RNA foci and dipeptide repeat proteins (DPRs), and TAR DNA-binding protein 43 (TDP-43) pathology. A large body of experimental work supports a role for microglial changes in C9-ALS. For example, human post-mortem analyses show microglial tissue infiltration, C9orf72 is strongly expressed in microglia, and loss of C9orf72 leads to lysosomal accumulation and altered pro-inflammatory responses in mice. Furthermore, recent single-cell transcriptomic analysis of human C9-ALS microglia reports an impaired transition of microglia towards a reactive cell state, which is supported by observations in C9-ALS organoid-derived microglia (oMG).
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     Cochlear amyloid beta 42–mediated hearing loss: A marker of preclinical Alzheimer’s disease#br# #br# #br#
    Dheyaa Al-Sallami, Shelley Tischkau, Raheem F. H. Al Aameri, Leonard P. Rybak
    2026, 21 (9):  4255-4256.  doi: 10.4103/NRR.NRR-D-25-01128
    Abstract ( 26 )   PDF (2847KB) ( 1 )   Save
    The emerging connection: As populations age, the link between age-related hearing loss (ARHL) and Alzheimer’s disease (AD) is emerging as one of the most urgent public health challenges of our time. Recent research analyzing 2946 communitydwelling adults revealed that hearing loss may contribute to nearly one-third of all new dementia cases — significantly higher than previous estimates. This epidemiological evidence suggests a mechanistic rather than coincidental relationship. Longitudinal studies show hearing loss precedes cognitive decline by 5–10 years. The implications are demographically profound. The yearly costs related to dementia are over $1.3 trillion, and untreated hearing loss adds another $133 billion in lost productivity. As a result, it has become essential to clarify the mechanistic link between these disorders. ARHL affects approximately one-third of adults over 65 years and rises to 75% in those over 80 years.In contrast, AD remains the leading cause of dementia, accounting for 60%–80% of all cases.
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    Alpha-synuclein structural variantsdriving tau pathology and disease interaction
    Chuanqi Sun
    2026, 21 (9):  4257-4258.  doi: 10.4103/NRR.NRR-D-25-01192
    Abstract ( 41 )   PDF (504KB) ( 8 )   Save
    Redefining neurodegenerative diseases: from isolated protein pathologies to intertwined disease networks: A common feature of neurodegenerative diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Lewy body dementia, and multiple system atrophy is the accumulation of misfolded, insoluble protein aggregates in specific neurons or glial cells. In AD, these aggregates are mainly manifested as neurofibrillary tangles composed of Tau protein, while in PD, they are mainly manifested as Lewy bodies composed of α-synuclein.
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    From neuronal marker to metabolic mediator: Expanding the functional landscape of N-acetylaspartate in the central nervous system and the periphery
    Maria Rosa Ciriolo, Fabio Ciccarone
    2026, 21 (9):  4259-4260.  doi: 10.4103/NRR.NRR-D-25-00931
    Abstract ( 48 )   PDF (1314KB) ( 3 )   Save
    N-acetylaspartate (NAA) is a non-proteinogenic derivative of L-aspartic acid and represents one of the most abundant metabolites in the human brain, reaching concentrations of approximately 10 mM. It is predominantly synthesized in neurons via the mitochondrial enzyme N-acetyltransferase 8-like (NAT8L), which catalyzes the transfer of an acetyl group from acetyl-CoA to L-aspartate. Consequently, NAA biosynthesis is tightly linked to neuronal mitochondrial activity. First identified in the mid-20th century through analyses of brain tissue extracts, NAA gained scientific interest due to its unusually high concentration in the central nervous system (CNS). Its relevance increased substantially with the advent of proton magnetic resonance spectroscopy in the 1980s, which enabled NAA non-invasive in vivo detection. Owing to its neuronal specificity, NAA has since become a well-established biomarker for assessing neuronal viability and function, with reduced levels reported in various neurodegenerative and neuroinflammatory disorders, including multiple sclerosis, Alzheimer’s disease, and traumatic brain injury.
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    Genetic elastic fiber disordersas neurovascular syndromes: An emerging perspective
    Francesc Jiménez-Altayó
    2026, 21 (9):  4261-4262.  doi: 10.4103/NRR.NRR-D-25-01159
    Abstract ( 35 )   PDF (6427KB) ( 3 )   Save
    Genetic elastic fiber diseases arise from inherited or de novo mutations in genes encoding elastic fiber components, such as elastin, fibrillin-1, and associated proteins, leading to abnormalities in their deposition, structure, or degradation. Historically, research has focused on systemic, non-neurological manifestations, which are more clinically apparent and often life-threatening, particularly cardiovascular complications. In contrast, potential involvement of the central nervous system (CNS) has received limited attention, even though the brain and spinal cord are richly vascularized structures, extensively perfused, and critically dependent on the integrity of their blood vessels.
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    Balancing mitochondrial health through inter-tissue neurotransmitter signaling
    Rebecca Cornell, Roger Pocock
    2026, 21 (9):  4263-4264.  doi: 10.4103/NRR.NRR-D-25-01191
    Abstract ( 38 )   PDF (506KB) ( 1 )   Save
    The ongoing health of our bodies is dependent on maintaining a balance between sympathetic and parasympathetic tone. These two branches of the autonomic nervous system work in concert to maintain homeostasis, protect the body against threats, and respond to internal and external stressors. As such, the appropriate and regulated activation of these systems is essential for maintaining health. The concept of balancing excitatory and inhibitory signals is conserved across species to the nematode Caenorhabditis elegans (C. elegans). Although C. elegans lack a distinct autonomic nervous system, they still rely on excitatory and inhibitory neurochemical signaling to mediate behavioral and biochemical processes. Two key players in this balancing act are the excitatory neurotransmitter, acetylcholine, and the inhibitory neurotransmitter, gammaaminobutyric acid (GABA). In our recent work, we have shown that coordination of these systems is essential for maintaining mitochondrial health across the body.
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    Factors influencing efficacy of neural stem and progenitor cell transplantation
    Angelina Baltazar, Jennifer N. Dulin
    2026, 21 (9):  4265-4266.  doi: 10.4103/NRR.NRR-D-25-01140
    Abstract ( 36 )   PDF (587KB) ( 5 )   Save
    Neural stem and progenitor cell (NSPC) transplantation holds promise for treating neurological injuries and diseases, yet the mechanisms underlying therapeutic efficacy remain incompletely understood. This Perspective highlights emerging evidence that synaptic connectivity between transplanted cells and host circuits is a key determinant of functional recovery. Drawing on analyses in spinal cord injury, traumatic brain injury, and Parkinson’s disease (PD), we argue that factors such as donor cell identity, graft-host compatibility, and neuronal phenotype critically influence outcomes. A deeper understanding of circuit integration will be essential for optimizing NSPC-based therapies and advancing clinicaltranslation.
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    Gene delivery to the mouse brain: Facilitating disease modeling and gene therapy
    Osama Ahmed, Aliaa Elshamy, Abraam Yakoub
    2026, 21 (9):  4267-4268.  doi: 10.4103/NRR.NRR-D-25-01793
    Abstract ( 38 )   PDF (611KB) ( 6 )   Save
    Gene delivery to the mouse brain is essential for neural circuit probing or therapeutic testing. We describe viral approaches for gene delivery to the mouse brain, and outline the applications and limitations of each approach, and strategies to mitigate the limitations. We provide a decisionoriented guide to the optimal vector and route combinations for the mouse brain, to facilitate studying brain functions or testing gene therapies in vivo.
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    Optogenetic innovations in stem cell therapy: Illuminating the path for transplanted cells after spinal cord injury
    María del Mar Sánchez-Martín, Victoria Moreno-Manzano, Esther Giraldo
    2026, 21 (9):  4269-4270.  doi: 10.4103/NRR.NRR-D-25-01817
    Abstract ( 41 )   PDF (1266KB) ( 8 )   Save
    Unleashing the regenerative capacity of the central nervous system following spinal cord injury (SCI) remains a challenging frontier in the field. Despite extensive efforts, the complex pathophysiology of SCI, characterized not only by the immediate damage of the primary injury but also by the subsequent cascades of events over time, presents significant obstacles to meaningful functional recovery. These processes vary significantly among SCI patients, further hindering the effectiveness of existing therapeutic interventions. The incidence of SCI varies worldwide, with approximately 25 new cases per million individuals annually, leading to long-lasting physical, psychological, and social consequences.
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    Surgical and anesthetic rewiring of the glymphatic system in postoperative cognitive dysfunction
    Bandy Chen
    2026, 21 (9):  4271-4272.  doi: 10.4103/NRR.NRR-D-25-01120
    Abstract ( 33 )   PDF (467KB) ( 4 )   Save
    Postoperative cognitive dysfunction (POCD) is a condition characterized by a variety of neurological deficits, including memory deficits, difficulty with attention and executive function, and behavioral changes or deliriumlike symptoms. These changes can be transient or long-lasting; however the exact mechanisms involved in POCD pathogenesis remain unclear. Well-established pathways that can contribute to POCD are neuroinflammation, blood-brain barrier disruption, and neurovascular dysfunction. An emerging candidate is the glymphatic system due to anesthesia’s profound effects on modulating glymphatic flow. This system is intimately linked to other brain processes, collectively referred to as the neuro-glial-vascular landscape. The central hypothesis linking POCD and the glymphatic system is that surgical stress and anesthesia impair glymphatic function, which results in the accumulation of neurotoxic waste products (e.g., amyloid-beta and tau) in the brain. While this accumulation may not lead to symptoms in every individual, people with baseline glymphatic dysfunction, such as older individuals or individuals with neurological disorders, may be more susceptible to POCD. This perspective delves into the surgical and anesthetic impairment of glymphatic function, how the disruption can lead to POCD, and possible therapeutic interventions to mitigate these effects.
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    A missing link in the METTL3 chain: Chaperone regulation of METTL3 as a BAG:HSP70 client protein
    Joseph M. Irvin, Gail V.W. Johnson
    2026, 21 (9):  4273-4274.  doi: 10.4103/NRR.NRR-D-25-01872
    Abstract ( 60 )   PDF (1571KB) ( 3 )   Save
    Following translation, newly synthesized proteins must navigate a turbulent free energy landscape that threatens to trap them in misfolded or nonfunctional conformation. To reach their native states, many proteins are assisted by molecular chaperones that transiently facilitate folding and assembly without being part of the final structure. One such molecular scaffold is the heat shock protein 70 (HSP70) chaperone family, which acts in concert with Bcl-2-associated athanogene (BAG) co-chaperones to regulate a wide array of clients. By directly binding both a BAG protein and a client substrate, HSP70 acts as a versatile platform able to identify, retain, and effectively neutralize misfolded or mislocalized proteins. BAG proteins act as the decision-makers in this system, and modular interchange of the BAG family members BAG1–BAG6 influences client retention, localization, and degrative fate depending on the BAG protein bound. In a previous review discussing the diverse roles of BAG family proteins in mediating central nervous system (CNS) homeostasis, we performed an interactome analysis using publicly available datasets for all BAG family proteins except for BAG4, due to its limited expression in CNS contexts. In addition to expected canonical associations with HSP70 family members and the E3 ligase C-terminus of Hsc70-interacting protein, we were surprised to observe methyltransferaselike 3 (METTL3) as a common interactor of all BAG proteins examined.
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    Complex bioactive nanofibrous dura mater promotes the repair of traumatic brain injury
    Siyu Chen, Xiaopei Zhang, Qingxia Guo, Yuying Yan, Manfei Fu, Yuanfei Wang, Tong Wu
    2026, 21 (9):  4275-4289.  doi: 10.4103/NRR.NRR-D-25-00621
    Abstract ( 45 )   PDF (16122KB) ( 3 )   Save
    Dura closure following surgery for traumatic brain injury is important to maintain the structural integrity of the brain and serve as a barrier to prevent infection and leakage of cerebrospinal fluid. Although an artificial dural mater can provide barrier capabilities, its performance in the repair of injured neural cells and neuroprotection during the secondary injury stage can be improved. Therefore, we designed and manufactured a multi-layer nanofibrous dura mater containing minocycline and insulin-like growth factor 1 using electrospinning technology to repair tissue following traumatic brain injury. The results showed that the multi-layer nanofibrous dura mater promoted neuronal process transection, hypoxia, and glucose deprivation, as well as survival and neurite extension of SH-SY5Y cells after oxidative stress injury. Minocycline hydrochloride and insulin growth factor 1 were separately incorporated into the fibers to facilitate their differential dual release for immunomodulation during the early stage of traumatic brain injury and provide neuroprotection during the repair process. In addition, the multi-layered nanofibrous dura mater promoted the increase in M2 polarization for microglia and the secretion of anti-inflammatory cytokines, which enhanced neural cell survival. Furthermore, we verified the antibacterial, anti-adhesion, barrier performance, anti-leakage, and biocompatibility capabilities of the multi-layered nanofibrous dura mater. Therefore, our multi-layered nanofibrous dura mater containing minocycline and insulin-like growth factor 1 has great potential as a substitute for dura mater and promotes nerve recovery following traumatic brain injury.
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    Biomaterial gels drive endogenous neurogenesis to support functional recovery after adult traumatic cortical injury
    Jinting Wu, Peng Hao, Hongmei Duan, Wen Zhao, Yudan Gao, Zhiqiang Cui, Zhaoyang Yang, Xiaoguang Li
    2026, 21 (9):  4290-4296.  doi: 10.4103/NRR.NRR-D-25-01291
    Abstract ( 78 )   PDF (21163KB) ( 6 )   Save

    Activation and neuronal differentiation of endogenous neural stem/progenitor cells within the hippocampal neurogenic niche (a neurogenic region) of the adult mammalian brain are considered potential bases for restoration of cognitive and memory functions. However, following traumatic cortical brain injury (i.e., injuries in a non-neurogenic region), the local microenvironment becomes hostile due to the presence of inhibitory factors such as inflammation, edema, and hypoxic–ischemic stress. These conditions hinder the migration and subsequent neuronal differentiation of activated neural stem/progenitor cells into the injured cortex. Numerous recent studies have confirmed that biomaterials can improve the microenvironment of the injured area and promote nerve regeneration. In this study, we report the findings obtained by injecting a biodegradable chitosan–gelatin–collagen gel into the cortical lesion area. We observed that the chitosan–gelatin–collagen gel established a permissive microenvironment for neural repair by suppressing inflammation and scar infiltration while promoting neovascularization. Thus, it enabled activated endogenous “seed” cells, i.e., neural stem/progenitor cells, to migrate into the cortical lesion area and generate new neurons and thereby facilitate functional recovery. These findings represent a novel biomaterial-based therapeutic strategy for the treatment of traumatic cortical brain injury, stroke, and other neurological disorders.

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    Mechanism by which low-intensity focused ultrasound promotes angiogenesis and neurogenesis after traumatic brain injury in a rat model via the OXA/MAPK signaling pathway
    Bingkai Ren, Junwei Kang, Peng Yao, Lianghua Huang, Yan Wang, Yang Bai, Zhen Feng
    2026, 21 (9):  4297-4310.  doi: 10.4103/NRR.NRR-D-24-01153
    Abstract ( 59 )   PDF (43105KB) ( 23 )   Save
    Low-intensity focused ultrasound is a type of ultrasound that primarily relies on cavitation and mechanical effects. It is non-invasive, transient, and well tolerated. Previous studies have confirmed that low-intensity focused ultrasound can reduce neuroinflammation after traumatic brain injury and exert neuroprotective effects. However, whether it can also induce angiogenesis and neurogenesis in the brain, as well as the underlying mechanisms, remains unclear. In this preclinical study, a rat model of traumatic brain injury was established using a controlled cortical impact device. The rats were then received 14 days of low-intensity focused ultrasound treatment targeting the thalamus. The results showed that low-intensity focused ultrasound effectively reduced cerebral edema and mitigated blood–brain barrier damage in rats with traumatic brain injury, leading to improved neurological function. Further investigation showed that low-intensity focused ultrasound significantly un-regulated Orexin-A/Orexin-A receptor 1 expression, and intraperitoneal administration of the Orexin-A receptor 1 inhibitor SB334867 prevented the neuroprotective effects of low-intensity focused ultrasound. Subsequent transcriptome sequencing revealed that low-intensity focused ultrasound activated the MAPK signaling pathway. Finally, in an in vitro cell injury model created using tumor necrosis factor-alpha, low-intensity focused ultrasound enhanced endothelial cell migration, stimulated angiogenesis, and supported hippocampal neuron migration and growth. Moreover, the MAPK signaling pathway inhibitor LY3214996 suppressed these effects. Taken together, our findings suggest that low-intensity focused ultrasound enhances angiogenesis and neurogenesis and improves neurological function following traumatic brain injury by regulating the expression of Orexin-A/Orexin-A receptor 1, which activates the MAPK signaling pathway. 
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    Semaglutide alleviates neuroinflammation and exerts neuroprotective effects by blocking IL-17/NLRP 3-mediated positive feedback between peripheral and innate immunocytes following traumatic brain injury
    Bin Zhang, Lu Kong, Yumei Wang, Wei He, Mengshi Yang, Xueling Zhang, Xiyu Chen, Yaxuan Zhang, Baiyun Liu, Miao Bai, Guangzhi Shi
    2026, 21 (9):  4311-4321.  doi: 10.4103/NRR.NRR-D-25-00990
    Abstract ( 71 )   PDF (35643KB) ( 4 )   Save
    Semaglutide, a long-acting glucagon-like peptide-1 receptor agonist, exhibits significant neuroprotective effects in stroke and neurodegenerative diseases. However, the anti-inflammatory and barrier-protective effects of semaglutide and the mechanisms underlying its effects following traumatic brain injury remain unclear. In this study, we used mice to establish a model of controlled cortical impact injury to investigate the roles and effects of semaglutide on neuroinflammation, the integrity and permeability of the blood– brain barrier, brain edema, and the recovery of neurological function after traumatic brain injury. Our results showed that semaglutide treatment alleviated interleukin-17/NOD-like receptor pyrin domain-containing 3-induced neuroinflammation and upregulated the expression of tight junction proteins, thereby reducing brain leakage and edema while promoting the recovery of neurological function. Furthermore, transmission electron microscopy assessments demonstrated that semaglutide maintained the ultrastructure of the blood–brain barrier, strengthening the tight junctions between endothelial cell membranes. Mechanistically, semaglutide alleviated inflammatory conditions by interrupting the positive-feedback loop of inflammation in peripheral and innate immune cells induced by interleukin-17/NOD-like receptor pyrin domain-containing 3. Collectively, our findings reveal the dual anti-inflammatory and neuroprotective roles of semaglutide, providing important preclinical evidence for its clinical application in the acute phase of traumatic brain injury. 
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    Critical ischemia duration thresholds in the rat middle cerebral artery occlusion model: Implications for drug screening
    Alba Puente-Sanz, Amanda Herrero-González, Diego Pérez-Rodríguez, José Manuel Gonzalo-Orden, Michal Letek, Berta Anuncibay-Soto, Arsenio Fernández-López
    2026, 21 (9):  4322-4330.  doi: 10.4103/NRR.NRR-D-24-00972
    Abstract ( 43 )   PDF (4776KB) ( 4 )   Save
    The growing incidence of stroke and the absence of drugs to fight its devastating consequences highlight the urgent need to identify therapeutic agents. The middle cerebral artery occlusion model is commonly used to screen new putative anti-stroke agents in rodents. However, differences in ischemia and reperfusion times result in differences in neurological deficit and infarct volume, two of the most commonly used parameters in preclinical assays. These differences make it difficult to select the optimal screening conditions. Here, we report a parallel study comparing behavior, infarct volume, and transcriptomic outcomes after 15 days of reperfusion in a rat middle cerebral artery occlusion model with mild (45 minutes) and moderate (60 minutes) ischemia. The behavioral assays revealed that motor and sensory responses, but not the infarct volume, are sensitive to slight variations in the time of ischemia. The transcriptomic profiling demonstrated striking changes in the number of up- and downregulated genes between mild and moderate ischemia. Gene Ontology analysis supported noteworthy differences between mild and moderate ischemia, particularly in genes related to protein synthesis and processing. Complementary quantitative polymerase chain reaction and western blotting assays confirmed these differences. These results indicate a threshold between mild and moderate ischemia, where changes in behavior and molecular responses mirror a substantial alteration in brain cell biology that appears critical for molecular screening. These findings pinpoint the critical role of selecting the appropriate ischemia model in preclinical stroke studies to enhance the translational relevance of the results and therapeutic strategies.
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    Mitophagy alleviates neuronal damage after subarachnoid hemorrhage: Role of autophagy-targeting chimera 4
    Yongzhi Zhang, Jianqiao Li, Qi Sun, Peichun Zhou, Pei Wu, Zhiyong Ji, Yuchen Li, Huaizhang Shi
    2026, 21 (9):  4331-4341.  doi: 10.4103/NRR.NRR-D-25-00705
    Abstract ( 46 )   PDF (29985KB) ( 1 )   Save
    This study investigated the role of autophagy-targeting chimera 4, a novel activator of autophagy that targets mitochondria, in a subarachnoid hemorrhage model. The data demonstrated that in an in vitro mitochondrial damage model, autophagy-targeting chimera 4 reversed carbonyl cyanide 3-chlorophenylhydrazone-induced mitochondrial membrane potential collapse and activated mitophagy. In the in vitro subarachnoid hemorrhage model, autophagy-targeting chimera 4 improved neuronal proliferation and migration during the acute phase and reduced neuronal apoptosis after subarachnoid hemorrhage. In the in vivo subarachnoid hemorrhage model, autophagy-targeting chimera 4 also decreased neuronal apoptosis during the acute phase, improved neurological function, and ultimately reduced long-term neuronal loss. Additionally, increased ring finger protein 144B expression after subarachnoid hemorrhage was associated with poor prognosis, and autophagy-targeting chimera 4 significantly inhibited ring finger protein 144B expression, thereby activating mitophagy and reducing neuronal apoptosis. The results also showed that the mitophagic marker parkin did not exert protective effects during the acute phase after subarachnoid hemorrhage and might be inhibited by ring finger protein 144B. Moreover, parkin inhibition did not interfere with the mitophagic or apoptotic effects of autophagy-targeting chimera 4. These findings not only confirm that autophagy-targeting chimera 4 exerts neuroprotective effects by targeting mitophagy after subarachnoid hemorrhage, but also demonstrate competitive inhibition between ring finger protein 144B and parkin, leading to poor prognosis in the acute phase after subarachnoid hemorrhage.
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    Intranasal and intracerebroventricular delivery of metabolically glycoengineered neural stem cells to enhance post–cardiac arrest brain recovery
    Xiao Liu, Zhulin Wang, Jian Du, Songah Chae, Subash Marasini, Madelynn McElroy, Kevin J. Yarema, Xiaofeng Jia
    2026, 21 (9):  4342-4351.  doi: 10.4103/NRR.NRR-D-25-00696
    Abstract ( 47 )   PDF (16189KB) ( 5 )   Save
    Cardiac arrest leads to global cerebral ischemia, causing significant neurological deficits with few effective treatments currently available. Neural stem cell (NSC) transplantation has shown therapeutic promise; however, challenges remain to achieve optimal and consistent delivery while maximizing cell functionality post-transplantation. Metabolic glycoengineering (MGE) has emerged as a novel technique to improve NSC viability and therapeutic efficacy by modifying their glycans. This report compares the effects of different delivery routes for this innovative approach of using MGE-modified NSCs (MGE-NSCs) to treat ischemic brain injury post–cardiac arrest. A total of 16 rats were subjected to 9-minute asphyxia cardiac arrest (4 weeks) and 21 rats subjected to 11-minute asphyxia cardiac arrest (3 days) to model severe and very severe brain injury, respectively. The MGE-NSCs were administered either intranasally or intracerebroventricularly (ICV) 3 hours after resuscitation. Neurological deficits and neurobehavior tests were assessed periodically after resuscitation. Neuronal damage was examined with Fluro-Jade C staining and cresyl violet staining. The transplanted MGE-NSCs were tracked using immunofluorescence staining. In the early phase of recovery, the ICV administration resulted in better neurological deficit scores shortly after resuscitation compared with the intranasal route. Three days post-resuscitation, MGE-NSCs were primarily located in the cortex and hippocampus, with a higher percentage in the ICV-treated group. However, by 4 weeks, rats treated with intranasal MGE-NSCs exhibited superior locomotor function and reduced anxiety-/depression-related behaviors compared with those receiving ICV-NSC therapy. This was accompanied by greater survival and distribution of MGE-NSCs to the cerebellum and brainstem, along with reduced microglia recruitment. MGE-NSCs administered via both delivery methods enhanced vascular angiogenesis, neuron differentiation, and synaptic plasticity. Overall, intranasal delivery was as effective or potentially superior to ICV for long-term recovery, whereas ICV conferred short-term advantages. These results highlight the potential of MGE-NSC therapy to enhance post–cardiac arrest recovery, advocating for tailored treatment strategies based on specific recovery phase goals.
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    Broca’s area, responsible for speech production, is regulated by lung function
    Siyu Cao, Wenwen Zhuang, Yuqian Hu, Shijun Qiu, Li-Hai Tan
    2026, 21 (9):  4352-4357.  doi: 10.4103/NRR.NRR-D-25-00685
    Abstract ( 58 )   PDF (3724KB) ( 1 )   Save
    For more than 150 years, Broca’s area—specifically, the pars opercularis and pars triangularis in the left inferior frontal gyrus—has been recognized as crucial for human speech production. However, it remains unknown why this region is recruited for speaking. Speech production involves not only conceptualization and motor planning but also respiration to provide the necessary airflow for creating sounds. Thus, the role of Broca’s area in speech may be shaped by the functionality and related brain regions of the lungs. To test this hypothesis, we recruited patients with chronic obstructive pulmonary disease and asked them to read words aloud while their brains were scanned using functional magnetic resonance imaging, with quantitative magnetic resonance imaging acquired separately. The chronic obstructive pulmonary disease patients exhibited altered cortical responses in the left inferior prefrontal cortex and other regions during speech tasks, and also had abnormal activation in cortical sites associated with breathing. In addition, using quantitative magnetic resonance imaging to generate longitudinal relaxation time (T1) maps as an index of brain microstructural changes, including dendritic maturation and myelination, we observed significantly longer longitudinal relaxation times in Broca’s area in the chronic obstructive pulmonary disease group than in the control group, suggesting reduced myelination and impaired microstructural integrity. Crucially, our data indicated that more severe dyspnea was associated with less well-developed microstructure in Broca’s area and weaker activation of this region. The present study indicates for the first time that the lungs may function to shape Broca’s area as the speaking center, providing novel evidence that pulmonary dysfunction can influence both the functional and structural properties of cortical language regions. These findings highlight the mechanistic role of the lung–brain axis in speech production and suggest potential targets for interventions to enhance speech performance.
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    Argonaute 2 stabilization of microRNAs controls adult neurogenesis and oligodendrogenesis
    Xianshuang Liu, Wanlong Pan, Michael Chopp, Baoyan Fan, Xinli Wang, Julie Landschoot-Ward, Min Wei, Qinge Lu, Helen Liu, William Golembieski, Sutapa Santra, Zheng Gang Zhang
    2026, 21 (9):  4358-4366.  doi: 10.4103/NRR.NRR-D-24-00043
    Abstract ( 33 )   PDF (3556KB) ( 1 )   Save
    MicroRNAs regulate neural stem cell function. Argonaute 2 protein, constituent of the RNA-induced silencing complex, plays an important role in regulating microRNA function for post-transcriptional gene silencing. Although Argonaute 2 and microRNAs are recognized as central regulators of RNA-induced silencing complex, their precise role in adult neural stem cell function has remained unclear. In particular, it was not known whether Argonaute 2 is required for sustaining neural stem cell proliferation, neurogenesis, and oligodendrogenesis in the adult brain, or how its loss might influence recovery after ischemic injury. The present study examined the effect of Argonaute 2 deletion in adult neural stem cells on neurogenesis and oligodendrogenesis. Adult transgenic mice with conditional and inducible ablation of Argonaute 2 in Ascl1-lineage neural stem cells exhibited the reduction of neurogenesis in the ventricular–subventricular zone of the lateral ventricle and in the subgranular zone of the dentate gyrus, as evidenced by a decrease in neural stem cell proliferation and neuroblast numbers. Argonaute 2 deletion also reduced oligodendrogenesis in the corpus callosum, as indicated by the reduction of oligodendrocyte progenitor cell proliferation and the number of mature oligodendrocytes. Additionally, deleting Argonaute 2 in adult neural stem cells of ischemic mice exacerbated impairments of sensorimotor and cognitive functions. Mechanistically, Argonaute 2 ablation in neural stem cells reduced the stability of mature microRNAs and downregulated genes involved in the Shh (Sonic Hedgehog), Notch, and TGFβ (transforming growth factor beta) signaling pathways, which regulate the functions of neural stem cells. Collectively, our study demonstrates that Argonaute 2 is essential for adult neural stem cell-mediated neurogenesis and oligodendrogenesis, with its deletion worsening recovery after ischemia. By revealing that Argonaute 2 stabilizes mature microRNAs, our work uncovers a novel mechanism of neural stem cell regulation and highlights Argonaute 2 as a potential therapeutic target for neurodegenerative and ischemic brain diseases.
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    Rictor/mTORC2 signaling pathway protects endogenous neural stem cells to promote recovery after spinal cord injury
    Kuileung Tong, Shiming Li, Guoliang Chen, Dacheng He, Chengkai Lin, Yuhang Li, Ningning Chen
    2026, 21 (9):  4367-4377.  doi: 10.4103/NRR.NRR-D-25-00544
    Abstract ( 54 )   PDF (36179KB) ( 1 )   Save
    Although endogenous neural stem cells represent a promising target for noninvasive spinal cord injury repair, inflammatory lesion environments frequently trigger their death. Our prior work identified necroptosis as a key death pathway for endogenous neural stem cells migrating to spinal cord injury lesions. Rapamycin-insensitive companion of mTOR (Rictor; a core component of the mechanistic target of rapamycin complex 2 [mTORC2] complex) regulates neural stem cell self-renewal and differentiation, and our preliminary data implicate it in spinal cord injury repair; however, its role in promoting endogenous neural stem cell survival post-spinal cord injury remains unclear. Here, we generated conditional endogenous neural stem cell-specific Rictor knockout mice using the Cre-loxP system. Although the endogenous neural stem cell-specific Rictor knockout mice displayed normal baseline spinal cord morphology and function, they exhibited impaired functional recovery after spinal cord injury compared with wild-type controls. This deficit correlated with elevated inflammatory responses and the increased susceptibility of endogenous neural stem cells to necroptosis. Mechanistically, lentiviral-mediated Rictor knockdown in neural stem cells in vitro impaired lysosomal function, leading to heightened sensitivity to tumor necrosis factor-alpha- and lipopolysaccharide-induced necroptosis. Collectively, these findings indicate that Rictor/mTORC2 signaling protects endogenous neural stem cells against receptor-interacting protein kinase 1-mediated necroptosis following spinal cord injury. Consequently, the modulation of intrinsic Rictor activity represents a potential therapeutic strategy to enhance endogenous neural stem cell survival and functional recovery post-spinal cord injury.
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    Hedgehog signaling activation rescues hypoxia-induced ferroptosis in human brain organoids 
    Simeng Yi, Min Huang, Chunmei Xian, Xi Kong, Shigang Yin, Jianhua Peng, Hongda Li, Yong Jiang, Bingqing Xie, Huangfan Xie
    2026, 21 (9):  4378-4389.  doi: 10.4103/NRR.NRR-D-25-00338
    Abstract ( 51 )   PDF (19364KB) ( 1 )   Save

    Fetal hypoxia disrupts neurodevelopment. In particular, the developing brain is extremely vulnerable to hypoxia injury; however, the specific vulnerable cell types and their underlying molecular mechanisms remain underexplored. In the present study, we established a human brain organoid model that reproduced the pathophysiological process of fetal hypoxia during early to mid-gestation. Through single-cell transcriptomic technology, we identified seven neural lineages in these organoids, including cortical progenitors and neurons. Further analysis revealed the specific responses to hypoxia among different types of cells regarding the mechanistic target of rapamycin complex 1 signaling pathway, fatty acid synthesis, the unfolded protein response, and the innate immune response. In terms of development, the maturation of glutamatergic and γ-aminobutyric acid-ergic neurons was significantly delayed after hypoxia exposure, whereas progenitor cells were less affected. In terms of function, we identified two subtypes of γ-aminobutyric acid-ergic neurons with different sensitivities to hypoxia. The more mature type 2 neurons were the most sensitive to hypoxia, which manifested as ferroptosis activation and impaired expression of neurite proteins (e.g., microtubule-associated protein 2). By contrast, the less mature type 1 neurons showed some tolerance to hypoxia. A mechanistic study revealed that pharmacological activation of the hedgehog pathway can inhibit ferroptosis and restore expression of the neurite protein microtubule-associated protein 2 in type 2 γ-aminobutyric acid-ergic neurons under hypoxia. Collectively, these findings delineate the lineage-specific patterns of hypoxia vulnerability and establish hedgehog pathway regulation as a potential target for neuroprotective strategies in fetal brain hypoxic injury.

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    Trans-activator of transcription-pre-B-cell leukemia transcription factor 1 alleviates Alzheimer’s disease by reducing neuronal insulin resistance and restoring energy homeostasis
    Xiangyuan Meng, Zinan Liu, Zhenhu Zhao, Lei Chen, Siyao Li, Qi Song, Ruihan Guo, Xin Zhang, Fanlei Meng, Hui Zhang, Li Tan, Xinpeng Liu, Yujie Wang, Feng Zhong, Run Liu, Tianlin Gao, Jinyu Liu
    2026, 21 (9):  4390-4405.  doi: 10.4103/NRR.NRR-D-25-01313
    Abstract ( 56 )   PDF (64461KB) ( 4 )   Save
    Alzheimer’s disease is characterized by hippocampal neuronal apoptosis, which leads to cognitive decline. The pathophysiology of Alzheimer’s disease is largely driven by disrupted cellular metabolism and insufficient neuronal energy supply. However, current treatments for Alzheimer’s disease remain limited because of side effects and disease complexity. Increasing evidence suggests that amyloid-β oligomer-induced neuronal insulin resistance and metabolic dysfunction play key roles in Alzheimer’s disease progression, yet their underlying mechanisms and therapeutic strategies remain unclear. In this translational preclinical study, we combined a case-control analysis, in vitro cell assays, and in vivo experiments using amyloid precursor protein/presenilin 1 transgenic mice to investigate whether transcriptional regulation of key regulatory factors restores neuronal energy supply and improves Alzheimer’s disease-induced pathology. The case-control analysis identified pre-B-cell leukemia transcription factor 1 as a crucial regulator of brain metabolic homeostasis in Alzheimer’s disease. We developed a blood–brain barrier-permeable trans-activator of transcription-pre-B-cell leukemia transcription factor 1 fusion protein to enhance pre-B-cell leukemia transcription factor 1 expression, with the aim of restoring neuronal energy supply and reducing apoptosis. Mechanistic investigations using Alzheimer’s disease models revealed that pre-B-cell leukemia transcription factor 1 transcriptionally upregulates insulin receptor substrate 1 by interacting with its promoter, which resulted in augmented insulin signaling. Trans-activator of transcription-pre-B-cell leukemia transcription factor 1 downregulated PDK4, significantly upregulated the expression of pyruvate dehydrogenase, and promoted mitochondrial oxidative phosphorylation activity, which inhibited the abnormally enhanced glycolytic flux, increased adenosine triphosphate production, and ultimately helped restore neuronal energy homeostasis. Therapeutic administration of trans-activator of transcription-pre-B-cell leukemia transcription factor 1 in amyloid precursor protein/presenilin 1 transgenic mice significantly enhanced cognitive performance, diminished hippocampal neuronal apoptosis, and mitigated amyloid-β deposition. No significant hepatotoxicity, nephrotoxicity, or other detectable adverse effects were observed within the dose ranges and time windows of administration. Taken together, we identified pre-B-cell leukemia transcription factor 1 as a crucial transcriptional regulator of neuronal energy metabolism in Alzheimer’s disease. Moreover, we elucidated the molecular mechanism through which the pre-B-cell leukemia transcription factor 1–insulin receptor substrate 1 signaling axis sustains metabolic homeostasis. Furthermore, we demonstrated that the blood–brain barrier-permeable trans-activator of transcription-pre-B-cell leukemia transcription factor 1 fusion protein constitutes a mechanistically innovative and highly translatable therapeutic strategy for Alzheimer’s disease. 
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    Genetic and pathway complexity in Alzheimer’s disease: Insights from multi-omic data about the immune response and mitochondrial function
    Xuan Xu, Jiang Li, Fei Wang, Ke Xue, Junwen He, Xiangyu Meng, Yin Shen
    2026, 21 (9):  4406-4423.  doi: 10.4103/NRR.NRR-D-25-00184
    Abstract ( 63 )   PDF (37789KB) ( 5 )   Save
    Despite recent developments, the genetics and biology of Alzheimer’s disease remain insufficiently characterized. As an important first step toward developing effective treatment strategies to slow or prevent Alzheimer’s disease onset, the identification of relevant genetic markers is crucial. In the present study, we analyzed transcriptomic and multi-omic datasets across multiple cohorts (the Alzheimer’s Disease Neuroimaging Initiative, Religious Orders Study and Rush Memory and Aging Project, Mount Sinai Brain Bank, and Mayo Clinic Alzheimer’s Disease Genetics Studies) using gene set enrichment analysis, machine learning algorithms, and polygenic risk scoring to identify gene sets relevant to Alzheimer’s disease risk and pathological features. For prioritized gene sets, we performed epigenome-wide association studies to assess DNA methylation patterns, and used multi-omic mediation analysis to characterize the causal gene regulatory networks. Overall, we identified several key gene sets relevant to Alzheimer’s disease pathology—particularly, those related to immune system function and mitochondrial dysfunction. Upregulated pathways, including neutrophil degranulation and tumor necrosis factor-α signaling pathways, correlated strongly with aspects of neuroinflammation in Alzheimer’s disease. By contrast, downregulated oxidative phosphorylation pathways further suggested mitochondrial dysfunction. Gene sets that contained mitochondrially located genes (e.g., SGK1 and LRRK1) were identified as significantly contributing to neurodegeneration. Moreover, genes such as CXCL1, TGFB2, and DUSP1 were consistently implicated in all datasets, thus emphasizing their involvement in immune modulation and mitochondrial function. The multimodal investigation outlined in the current study represents useful steps toward comprehending the genetic architecture of Alzheimer’s disease, including an expanded understanding of the spatial interactions of genes associated with disease susceptibility. Mitochondrial dysfunction and immune modulation were pathological pathways that converged on Alzheimer’s disease and future treatment novel options. Using the frameworks provided in the current comprehensive study, we present opportunities to explore targeted treatment strategies that may alter immune systems and mitochondrial function to optimize treatment outcomes for individuals at increased risk of or living with Alzheimer’s disease. 
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    Hippocampal neural stem cell–derived extracellular vesicles modulate microglia to promote resilience against tau oligomers
    Salvatore Saieva†, Pietro Scaduto, Anna Fracassi, Jutatip Guptarak, Wen-Ru Zhang, Kathia Johnson, Daniel C. Jupiter, Michela Marcatti, Olga Zolochevska, Giulio Taglialatela, Maria-Adelaide Micci
    2026, 21 (9):  4424-4434.  doi: 10.4103/NRR.NRR-D-25-00195
    Abstract ( 40 )   PDF (56262KB) ( 1 )   Save
    Neural stem cells and adult hippocampal neurogenesis modulate synaptic plasticity and cognitive function. Neural stem cells secrete extracellular vesicles – microvesicles carrying biomolecular cargos – that modulate the function of other cells and contribute to homeostasis and plasticity in the central nervous system. Alzheimer’s disease is marked by a reduction of neural stem cells in the hippocampus dentate gyrus. While increased neural stem cells often correlate with better learning and memory, neurogenesis alone does not always preserve these processes, indicating that other mechanisms involving neural stem cells support memory. It has been shown that intracerebroventricular delivery of neural stem cell-derived small extracellular vesicles in wild-type mice reduces cognitive decline and toxic oligomer binding to synapses. We hypothesize that adequate neural stem cell numbers support neural stem cell–derived small extracellular vesicles protection of synapses against Alzheimer’s disease toxic oligomers. Here, we show that elements of immune response in the central nervous system, particularly microglia, may contribute to this protective effect. Specifically, fluorescence-labeled small extracellular vesicles injected into wild-type mice brains were taken up by microglia, with only neural stem cell–derived small extracellular vesicles causing increased microglial activation, indicated by CD68 immunostaining. RNA-sequencing data showed selective activation of immune pathways in microglia by neural stem cell-derived small extracellular vesicles, leading to greater activation and higher Tau uptake 24 hours post-neural stem cell–derived small extracellular vesicle administration. Single-nuclei RNA-sequencing of hippocampal microglia gene revealed modulation related to lysosomal activity, supporting neural stem cell–derived small extracellular vesicle-induced neuroprotection via microglia. This study uncovers a novel mechanism through which neural stem cell–derived small extracellular vesicles enhance microglial activity and provide neuroprotection in the hippocampus. Our data demonstrates that neural stem cell–derived small extracellular vesicle uptake by microglia leads to increased microglial activation and improved uptake of Tau oligomers by microglia, suggesting that neural stem cell–derived small extracellular vesicles may prime microglia for a more effective immune response. These results support the hypothesis that neural stem cell–derived small extracellular vesicle-induced modulation of microglial function is crucial for preserving neuronal integrity and mitigating neurodegenerative processes. By elucidating the interactions between neural stem cell–derived small extracellular vesicles and microglia, our study opens new avenues for developing therapeutic strategies aimed at boosting microglial function and addressing neurodegenerative diseases such as Alzheimer’s disease.
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    Disulfidptosis contributes to rotenone-induced dopaminergic neuron damage
    Wenqi Ye, Qifu Zhang, Wei Ge, Haoyin Liu, Yaohui Shan, Feng Ye, Xiaogang Wang, Yuanpeng Zhao, Guorong Dan, Mingliang Chen, Yan Sai
    2026, 21 (9):  4435-4446.  doi: 10.4103/NRR.NRR-D-25-00024
    Abstract ( 60 )   PDF (11275KB) ( 4 )   Save

    Parkinson’s disease is a neurodegenerative disorder whose pathogenesis remains incompletely understood. Rotenone exposure is reportedly associated with Parkinson’s disease. In addition, disulfidptosis is a newly identified form of cell death. Interestingly, an analysis of the Gene Expression Omnibus Parkinson’s disease database indicated that approximately 30 genes that are significantly altered in patients with Parkinson’s disease are associated with disulfidptosis. In the present study, using proteomics, a number of important proteins related to disulfidptosis were identified as significantly altered in rotenone-exposed dopaminergic neurons. Further analysis revealed that the formation of abnormal disulfide bonds was also increased in rotenone-exposed dopaminergic neurons. The protein expression of solute carrier family 7 member 11 and amino acid transporter heavy chain SLC3A2 was upregulated in rotenone-exposed dopaminergic neurons, and was correlated with extracellular matrix protein 1 protein expression. These findings indicate that in rotenone-exposed PC12 cells, a cystine influx is triggered, and the conversion of cystine to cysteine is inhibited by a reduction in the oxidized nicotinamide adenine dinucleotide phosphate/reduced nicotinamide adenine dinucleotide phosphate ratio, which leads to cystine accumulation. This excessive accumulation of cystine then promotes the formation of abnormal disulfide bonds in cells, ultimately resulting in disulfidptosis of rotenone-exposed dopaminergic neurons. In this process, the Ras-related C3 botulinum toxin substrate 1/WAVE regulatory complex/actin-related protein 2/3 pathway was markedly activated, which led to the collapse of the cytoskeleton in rotenone-exposed PC12 cells. Together, our findings suggest that rotenone may induce solute carrier family 7 member 11 expression through extracellular matrix protein 1 activation to cause cystine accumulation, which results in disulfidptosis characterized by cytoskeleton collapse. The present results provide new perspectives for research into neurodegenerative diseases.

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    Molecular pathways underlying amyloid precursor protein–mediated regulation of adult-born neurons
    Haidong Hu, Huidong Li, Yu Chen, Jianwen Zhou, Jian Chen, Qihong Tang, Xiaoshan Chen, Jinxiang Jiang, Mengyao Sun, Dongjing Jia, Wenyuan Xie, Cheng Long, Li Yang
    2026, 21 (9):  4447-4456.  doi: 10.4103/NRR.NRR-D-25-00175
    Abstract ( 36 )   PDF (6025KB) ( 1 )   Save
    Cleavage of amyloid precursor protein (APP) produces toxic amyloid-beta peptides, which play a critical role in the pathogenesis of Alzheimer’s disease. Neuronal loss is a key feature of Alzheimer’s disease. Despite the importance of APP in the proliferation of neural progenitors and the survival of adult-born granule cells in the dentate gyrus, little is known about the effect of APP deficiency on neuronal electrophysiological activities and the survival of newly born neurons. Utilizing whole-cell patch-clamp recording in combination with retroviral labeling and immunofluorescent staining in Alzheimer’s disease model mice with App knockout (App–/–), we show that APP deficiency increased the number of adult-born granule cells at 4 weeks post-injection, but did not affect their intrinsic excitability or miniature current activity. In contrast, at 10 weeks post-injection, adult-born granule cells showed increased abundance and intrinsic excitability that were associated with abnormal dendritic morphology, increased miniature excitatory- and inhibitory-synaptic transmission, and decreased potassium-chloride-cotransporter 2 expression. Compared with adult-born granule cells at 10 week post-injection, mature granule cells exhibited decreased intrinsic excitability and potassium-chloride-cotransporter 2 expression alongside increased apoptosis in App–/– mice. Additionally, although App–/–mice showed abnormal freezing behavior and elevated mature granule cell activation during contextual fear conditioning, adult-born granule cells were not recruited in either App–/– or wild-type control mice. Taken together, these findings suggest that APP is required for adult-born granule cell maturation and that APP deficiency induces excitotoxicity in adult-born granule cells at 10 weeks post-injection, promoting subsequent apoptosis of mature granule cells. 
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    A2 astrocyte polarization mediates ketogenic diet protection of blood–central nervous system barriers in experimental autoimmune encephalomyelitis.
    Qianye Zhang, Mingxiao Zheng, Hans-Christian Siebert, Qingpeng Wang, Ruiyan Zhang, Ning Zhang
    2026, 21 (9):  4457-4473.  doi: 10.4103/NRR.NRR-D-25-00062
    Abstract ( 43 )   PDF (9657KB) ( 2 )   Save

    Disruption of the blood–brain barrier and blood-spinal cord barrier is a fundamental pathological feature of multiple sclerosis progression. The ketogenic diet has a high therapeutic potential for patients with multiple sclerosis. We previously reported that treating experimental autoimmune encephalomyelitis mice with ketogenic diet results in anti-neuroinflammation and neuroprotection. However, the impact of ketogenic diet administration on the blood–brain barrier/blood–spinal cord barrier in MS remains unclear. Here, we investigated the effects of ketogenic diet on the blood–brain barrier/blood–spinal cord barrier integrity and the possible underlying mechanisms. We established a 24-day continuous experimental autoimmune encephalomyelitis mouse model with or without ketogenic diet and performed β-hydroxybutyrate assay kit histological analysis, quantitative reverse transcription-polymerase chain reaction, and western blot to examine experimental autoimmune encephalomyelitis pathological hallmarks, glial cell activation status, and intracellular signaling pathway alterations. Our results showed that ketogenic diet inhibited demyelination, suppressed astrocyte and microglial activation, and modulated the balance of matrix metalloproteinases/tissue inhibitors of metalloproteinases in the central nervous system of experimental autoimmune encephalomyelitis mice. Ketogenic diet upregulated tight junction proteins (occludin, claudin-1, and ZO-1) and adherens junction proteins (VE-cadherin and β-catenin) in the spinal cord, cerebellum, and cortex of experimental autoimmune encephalomyelitis mice. Notably, we found that ketogenic diet protects the blood–brain barrier/blood–spinal cord barrier integrity by modulating astrocyte polarization from the A1 phenotype to A2 phenotype and modifying the inflammatory milieu (downregulating pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, and interleukin-6, and upregulating anti-inflammatory cytokines such as transforming growth factor-β and interleukin-4) by inhibition of class I histone deacetylase 3/STAT3/nuclear factor kappa B (NF-κB)/NOD-, LRR- and pyrin domain-containing protein 3 and activation of PI3K/AKT signaling pathways. Furthermore, ketogenic diet downregulated key chemokines (C–X–C motif chemokine ligand 10, C–X–C motif chemokine ligand 12, C–C motif chemokine ligand 2, and C–C motif chemokine ligand 5) and receptor C–C motif chemokine receptor 2 expression throughout the central nervous system, suggesting an impaired capacity for leukocyte recruitment. Ketogenic diet suppressed astrocytic NOD-, LRR- and pyrin domain-containing protein 3 inflammasome activation, as evidenced by reduced NOD-, LRR- and pyrin domain-containing protein 3/glial fibrillary acidic protein co-localization. In summary, the ketogenic diet promotes neuroprotection in the experimental autoimmune encephalomyelitis model by inhibiting A1 astrogliogenesis and protecting the integrity of the blood–brain barrier/blood-spinal cord barrier.

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    Two-sample Mendelian randomization study of gut microbiota and inflammatory proteins: Predictive, preventive, and personalized treatment for migraine
    Ruolan Ma, Haiyan An, Yi Feng
    2026, 21 (9):  4474-4480.  doi: 10.4103/NRR.NRR-D-25-01711
    Abstract ( 65 )   PDF (5447KB) ( 2 )   Save

    The human gut microbiota is increasingly recognized as a significant factor in the pathogenesis of migraine, potentially via inflammatory pathways. Identifying specific human gut microbiota components associated with migraines, along with the investigation of particular inflammatory proteins, is essential for advancing primary prediction, targeted prevention, and personalized treatment strategies for migraines. We conducted a two-sample Mendelian randomization study using publicly available summary statistics from genome-wide association studies. Data for 473 human gut microbiota taxa were obtained from the Finnish national health survey conducted by the National Institute for Health and Welfare study (FINRISK, n = 5959 European participants). Genome-wide association study data (https://www.ebi.ac.uk/gwas/) for 91 circulating inflammatory proteins were obtained from 14,824 participants across 11 cohorts using the Olink Target 96 Inflammation panel. Migraine outcome data were obtained from the FinnGen R12 release, with cases defined using ICD-10 code G43. All genome-wide association study analyses were adjusted for sex, age, genotyping batch, and 10 genetic principal components to control population stratification (genomic inflation factors: 1.00–1.05). Inverse variance-weighted Mendelian randomization was the primary analysis method, with Mendelian randomization-Egger, weighted median, and mode-based methods as sensitivity analyses. Two-step Mendelian randomization mediation analysis quantified the proportion of the effects of human gut microbiota on migraine that are mediated through inflammatory proteins. Thirty-seven bacterial genera were found to be associated with migraine using the inverse variance-weighted method. Of these, 18 genera exhibited a negative association, while 19 genera demonstrated a positive association with migraine risk. Additionally, eight inflammatory proteins were found to increase the risk of migraine. Among human gut microbiota, four were observed to reduce inflammatory protein levels, whereas another four were associated with increased inflammatory protein levels. Additionally, five gut microbiota were identified to influence migraine through inflammatory proteins in both Mendelian randomization analyses. Specifically, Actinobacteria, Brachyspiraceae, CAG-269 sp001915995, and Paraglaciecola were found to affect migraine outcomes via inflammatory proteins, with mediation proportions of 12%, 19%, 15.5%, and 6.7%, respectively. Lawsonibacter sp002161175 was identified to influence migraine risk through Oncostatin-M and SLAM, with mediation proportions of 15.6% and 11.3%, respectively. Our study elucidated the role of specific human gut microbiota alterations in the pathogenesis of migraine and highlighted the mediating effects of inflammatory proteins. Targeting these particular human gut microbiota alterations offers a promising strategy for predictive, preventive, and personalized medicine in migraine management, resulting in substantial clinical advancements.

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