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15 February 2026, Volume 21 Issue 2 Previous Issue   

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Metabolic reprogramming of astrocytes: Emerging roles of lactate Zeyu Liu, Yijian Guo, Ying Zhang, Yulei Gao, Bin Ning 2026, 21 (2):  421-432.  doi: 10.4103/NRR.NRR-D-24-00776 Abstract ( 92 )   PDF (9490KB) ( 69 )   Save Lactate serves as a key energy metabolite in the central nervous system, facilitating essential brain functions, including energy supply, signaling, and epigenetic modulation. Moreover, it links epigenetic modifications with metabolic reprogramming. Nonetheless, the specific mechanisms and roles of this connection in astrocytes remain unclear. Therefore, this review aims to explore the role and specific mechanisms of lactate in the metabolic reprogramming of astrocytes in the central nervous system. The close relationship between epigenetic modifications and metabolic reprogramming was discussed. Therapeutic strategies for targeting metabolic reprogramming in astrocytes in the central nervous system were also outlined to guide future research in central nervous system diseases. In the nervous system, lactate plays an essential role. However, its mechanism of action as a bridge between metabolic reprogramming and epigenetic modifications in the nervous system requires future investigation. The involvement of lactate in epigenetic modifications is currently a hot research topic, especially in lactylation modification, a key determinant in this process. Lactate also indirectly regulates various epigenetic modifications, such as N6-methyladenosine, acetylation, ubiquitination, and phosphorylation modifications, which are closely linked to several neurological disorders. In addition, exploring the clinical applications and potential therapeutic strategies of lactic acid provides new insights for future neurological disease treatments. Related Articles | Metrics

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Targeting the brain’s glymphatic pathway: A novel therapeutic approach for cerebral small vessel disease Yuhui Ma, Yan Han 2026, 21 (2):  433-442.  doi: 10.4103/NRR.NRR-D-24-00821 Abstract ( 44 )   PDF (5019KB) ( 68 )   Save Cerebral small vessel disease encompasses a group of neurological disorders characterized by injury to small blood vessels, often leading to stroke and dementia. Due to its diverse etiologies and complex pathological mechanisms, preventing and treating cerebral small vessel vasculopathy is challenging. Recent studies have shown that the glymphatic system plays a crucial role in interstitial solute clearance and the maintenance of brain homeostasis. Increasing evidence also suggests that dysfunction in glymphatic clearance is a key factor in the progression of cerebral small vessel disease. This review begins with a comprehensive introduction to the structure, function, and driving factors of the glymphatic system, highlighting its essential role in brain waste clearance. Afterwards, cerebral small vessel disease was reviewed from the perspective of the glymphatic system, after which the mechanisms underlying their correlation were summarized. Glymphatic dysfunction may lead to the accumulation of metabolic waste in the brain, thereby exacerbating the pathological processes associated with cerebral small vessel disease. The review also discussed the direct evidence of glymphatic dysfunction in patients and animal models exhibiting two subtypes of cerebral small vessel disease: arteriolosclerosis-related cerebral small vessel disease and amyloid-related cerebral small vessel disease. Diffusion tensor image analysis along the perivascular space is an important noninvasive tool for assessing the clearance function of the glymphatic system. However, the effectiveness of its parameters needs to be enhanced. Among various nervous system diseases, including cerebral small vessel disease, glymphatic failure may be a common final pathway toward dementia. Overall, this review summarizes prevention and treatment strategies that target glymphatic drainage and will offer valuable insight for developing novel treatments for cerebral small vessel disease. Related Articles | Metrics

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Microglial intervention in ischemic stroke: Roles and intervention strategies Cuiling Ji, Lixinbei Sheng, Kaijun Han, Ping Yuan, Wei Li, Lu Chen, Yongyue Gao 2026, 21 (2):  443-454.  doi: 10.4103/NRR.NRR-D-24-01166 Abstract ( 70 )   PDF (14948KB) ( 29 )   Save Ischemic stroke is a major cause of neurological deficits and high disability rate. As the primary immune cells of the central nervous system, microglia play dual roles in neuroinflammation and tissue repair following a stroke. Their dynamic activation and polarization states are key factors that influence the disease process and treatment outcomes. This review article investigates the role of microglia in ischemic stroke and explores potential intervention strategies. Microglia exhibit a dynamic functional state, transitioning between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. This duality is crucial in ischemic stroke, as it maintains a balance between neuroinflammation and tissue repair. Activated microglia contribute to neuroinflammation through cytokine release and disruption of the blood–brain barrier, while simultaneously promoting tissue repair through anti-inflammatory responses and regeneration. Key pathways influencing microglial activation include Toll-like receptor 4/nuclear factor kappa B, mitogen-activated protein kinases, Janus kinase/signal transducer and activator of transcription, and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathways. These pathways are targets for various experimental therapies aimed at promoting M2 polarization and mitigating damage. Potential therapeutic agents include natural compounds found in drugs such as minocycline, as well as traditional Chinese medicines. Drugs that target these regulatory mechanisms, such as small molecule inhibitors and components of traditional Chinese medicines, along with emerging technologies such as single-cell RNA sequencing and spatial transcriptomics, offer new therapeutic strategies and clinical translational potential for ischemic stroke. Related Articles | Metrics

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Neural circuit mechanisms of epilepsy: Maintenance of homeostasis at the cellular, synaptic, and neurotransmitter levels Xueqing Du, Yi Wang, Xuefeng Wang, Xin Tian, Wei Jing 2026, 21 (2):  455-465.  doi: 10.4103/NRR.NRR-D-24-00537 Abstract ( 51 )   PDF (2268KB) ( 49 )   Save Epilepsy, a common neurological disorder, is characterized by recurrent seizures that can lead to cognitive, psychological, and neurobiological consequences. The pathogenesis of epilepsy involves neuronal dysfunction at the molecular, cellular, and neural circuit levels. Abnormal molecular signaling pathways or dysfunction of specific cell types can lead to epilepsy by disrupting the normal functioning of neural circuits. The continuous emergence of new technologies and the rapid advancement of existing ones have facilitated the discovery and comprehensive understanding of the neural circuit mechanisms underlying epilepsy. Therefore, this review aims to investigate the current understanding of the neural circuit mechanisms in epilepsy based on various technologies, including electroencephalography, magnetic resonance imaging, optogenetics, chemogenetics, deep brain stimulation, and brain–computer interfaces. Additionally, this review discusses these mechanisms from three perspectives: structural, synaptic, and transmitter circuits. The findings reveal that the neural circuit mechanisms of epilepsy encompass information transmission among different structures, interactions within the same structure, and the maintenance of homeostasis at the cellular, synaptic, and neurotransmitter levels. These findings offer new insights for investigating the pathophysiological mechanisms of epilepsy and enhancing its clinical diagnosis and treatment. Related Articles | Metrics

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Tryptophan metabolism and ischemic stroke: An intricate balance Chongjie Yao, Dong Xie, Yuchen Zhang, Yuanhao Shen, Pingping Sun, Zhao Ma, Jin Li, Jiming Tao, Min Fang 2026, 21 (2):  466-477.  doi: 10.4103/NRR.NRR-D-24-00777 Abstract ( 44 )   PDF (1455KB) ( 29 )   Save Ischemic stroke, which is characterized by hypoxia and ischemia, triggers a cascade of injury responses, including neurotoxicity, inflammation, oxidative stress, disruption of the blood–brain barrier, and neuronal death. In this context, tryptophan metabolites and enzymes, which are synthesized through the kynurenine and 5-hydroxytryptamine pathways, play dual roles. The delicate balance between neurotoxic and neuroprotective substances is a crucial factor influencing the progression of ischemic stroke. Neuroprotective metabolites, such as kynurenic acid, exert their effects through various mechanisms, including competitive blockade of N-methyl-D-aspartate receptors, modulation of α7 nicotinic acetylcholine receptors, and scavenging of reactive oxygen species. In contrast, neurotoxic substances such as quinolinic acid can hinder the development of vascular glucose transporter proteins, induce neurotoxicity mediated by reactive oxygen species, and disrupt mitochondrial function. Additionally, the enzymes involved in tryptophan metabolism play major roles in these processes. Indoleamine 2,3-dioxygenase in the kynurenine pathway and tryptophan hydroxylase in the 5-hydroxytryptamine pathway influence neuroinflammation and brain homeostasis. Consequently, the metabolites generated through tryptophan metabolism have substantial effects on the development and progression of ischemic stroke. Stroke treatment aims to restore the balance of various metabolite levels; however, precise regulation of tryptophan metabolism within the central nervous system remains a major challenge for the treatment of ischemic stroke. Therefore, this review aimed to elucidate the complex interactions between tryptophan metabolites and enzymes in ischemic stroke and develop targeted therapies that can restore the delicate balance between neurotoxicity and neuroprotection. Related Articles | Metrics

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Exosomes in neurodegenerative diseases: Therapeutic potential and modification methods Hongli Chen, Na Li, Yuanhao Cai, Chunyan Ma, Yutong Ye, Xinyu Shi, Jun Guo, Zhibo Han, Yi Liu, Xunbin Wei 2026, 21 (2):  478-490.  doi: 10.4103/NRR.NRR-D-24-00720 Abstract ( 55 )   PDF (4672KB) ( 75 )   Save In recent years, exosomes have garnered extensive attention as therapeutic agents and early diagnostic markers in neurodegenerative disease research. Exosomes are small and can effectively cross the blood–brain barrier, allowing them to target deep brain lesions. Recent studies have demonstrated that exosomes derived from different cell types may exert therapeutic effects by regulating the expression of various inflammatory cytokines, mRNAs, and disease-related proteins, thereby halting the progression of neurodegenerative diseases and exhibiting beneficial effects. However, exosomes are composed of lipid bilayer membranes and lack the ability to recognize specific target cells. This limitation can lead to side effects and toxicity when they interact with nonspecific cells. Growing evidence suggests that surface-modified exosomes have enhanced targeting capabilities and can be used as targeted drug-delivery vehicles that show promising results in the treatment of neurodegenerative diseases. In this review, we provide an up-to-date overview of existing research aimed at devising approaches to modify exosomes and elucidating their therapeutic potential in neurodegenerative diseases. Our findings indicate that exosomes can efficiently cross the blood–brain barrier to facilitate drug delivery and can also serve as early diagnostic markers for neurodegenerative diseases. We introduce the strategies being used to enhance exosome targeting, including genetic engineering, chemical modifications (both covalent, such as click chemistry and metabolic engineering, and non-covalent, such as polyvalent electrostatic and hydrophobic interactions, ligand-receptor binding, aptamer-based modifications, and the incorporation of CP05- anchored peptides), and nanomaterial modifications. Research into these strategies has confirmed that exosomes have significant therapeutic potential for neurodegenerative diseases. However, several challenges remain in the clinical application of exosomes. Improvements are needed in preparation, characterization, and optimization methods, as well as in reducing the adverse reactions associated with their use. Additionally, the range of applications and the safety of exosomes require further research and evaluation. Related Articles | Metrics

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Neuromodulation techniques for modulating cognitive function: Enhancing stimulation precision and intervention effects Hanwen Cao, Li Shang, Deheng Hu, Jianbing Huang, Yu Wang, Ming Li, Yilin Song, Qianzi Yang, Yan Luo, Ying Wang, Xinxia Cai, Juntao Liu 2026, 21 (2):  491-501.  doi: 10.4103/NRR.NRR-D-24-00836 Abstract ( 49 )   PDF (3526KB) ( 70 )   Save Neuromodulation techniques effectively intervene in cognitive function, holding considerable scientific and practical value in fields such as aerospace, medicine, life sciences, and brain research. These techniques utilize electrical stimulation to directly or indirectly target specific brain regions, modulating neural activity and influencing broader brain networks, thereby regulating cognitive function. Regulating cognitive function involves an understanding of aspects such as perception, learning and memory, attention, spatial cognition, and physical function. To enhance the application of cognitive regulation in the general population, this paper reviews recent publications from the Web of Science to assess the advancements and challenges of invasive and non-invasive stimulation methods in modulating cognitive functions. This review covers various neuromodulation techniques for cognitive intervention, including deep brain stimulation, vagus nerve stimulation, and invasive methods using microelectrode arrays. The non-invasive techniques discussed include transcranial magnetic stimulation, transcranial direct current stimulation, transcranial alternating current stimulation, transcutaneous electrical acupoint stimulation, and time interference stimulation for activating deep targets. Invasive stimulation methods, which are ideal for studying the pathogenesis of neurological diseases, tend to cause greater trauma and have been less researched in the context of cognitive function regulation. Non-invasive methods, particularly newer transcranial stimulation techniques, are gentler and more appropriate for regulating cognitive functions in the general population. These include transcutaneous acupoint electrical stimulation using acupoints and time interference methods for activating deep targets. This paper also discusses current technical challenges and potential future breakthroughs in neuromodulation technology. It is recommended that neuromodulation techniques be combined with neural detection methods to better assess their effects and improve the accuracy of non-invasive neuromodulation. Additionally, researching closed-loop feedback neuromodulation methods is identified as a promising direction for future development. Related Articles | Metrics

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What is the pathophysiology of inflammation-induced cortical injury in the perinatal brain? Sharmony B. Kelly, Alistair J. Gunn, Rodney W. Hunt, Robert Galinsky 2026, 21 (2):  502-505.  doi: 10.4103/NRR.NRR-D-24-01091 Abstract ( 29 )   PDF (4440KB) ( 36 )   Save Perinatal exposure to infection/inflammation is highly associated with neural injury, and subsequent impaired cortical growth, disturbances in neuronal connectivity, and impaired neurodevelopment. However, our understanding of the pathophysiological substrate underpinning these changes in brain structure and function is limited. The objective of this review is to summarize the growing evidence from animal trials and human cohort studies that suggest exposure to infection/ inflammation during the perinatal period promotes regional impairments in neuronal maturation and function, including loss of high-frequency electroencephalographic activity, and reduced growth and arborization of cortical dendrites and dendritic spines resulting in reduced cortical volume. These inflammation-induced disturbances to neuronal structure and function are likely to underpin subsequent disturbances to cortical development and connectivity in fetuses and/or newborns exposed to infection/inflammation during the perinatal period, leading, in the long term, to impaired neurodevelopment. The combined use of early electroencephalography monitoring with neuroimaging techniques that enable detailed evaluation of brain microstructure, and the use of therapeutics that successfully target systemic and central nervous system inflammation could provide an effective strategy for early detection and therapeutic intervention. Related Articles | Metrics

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Neuromodulation technologies improve functional recovery after brain injury: From bench to bedside Mei Liu, Yijing Meng, Siguang Ouyang, Meng’ai Zhai, Likun Yang, Yang Yang, Yuhai Wang 2026, 21 (2):  506-520.  doi: 10.4103/NRR.NRR-D-24-00652 Abstract ( 46 )   PDF (3515KB) ( 69 )   Save Spontaneous recovery frequently proves maladaptive or insufficient because the plasticity of the injured adult mammalian central nervous system is limited. This limited plasticity serves as a primary barrier to functional recovery after brain injury. Neuromodulation technologies represent one of the fastest-growing fields in medicine. These techniques utilize electricity, magnetism, sound, and light to restore or optimize brain functions by promoting reorganization or long-term changes that support functional recovery in patients with brain injury. Therefore, this review aims to provide a comprehensive overview of the effects and underlying mechanisms of neuromodulation technologies in supporting motor function recovery after brain injury. Many of these technologies are widely used in clinical practice and show significant improvements in motor function across various types of brain injury. However, studies report negative findings, potentially due to variations in stimulation protocols, differences in observation periods, and the severity of functional impairments among participants across different clinical trials. Additionally, we observed that different neuromodulation techniques share remarkably similar mechanisms, including promoting neuroplasticity, enhancing neurotrophic factor release, improving cerebral blood flow, suppressing neuroinflammation, and providing neuroprotection. Finally, considering the advantages and disadvantages of various neuromodulation techniques, we propose that future development should focus on closed-loop neural circuit stimulation, personalized treatment, interdisciplinary collaboration, and precision stimulation. Related Articles | Metrics

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Optogenetic approaches for neural tissue regeneration: A review of basic optogenetic principles and target cells for therapy Davletshin Eldar, Sufianov Albert, Ageeva Tatyana, Sufianova Galina, Rizvanov Albert, Mukhamedshina Yana 2026, 21 (2):  521-533.  doi: 10.4103/NRR.NRR-D-24-00685 Abstract ( 82 )   PDF (2792KB) ( 81 )   Save Optogenetics has revolutionized the field of neuroscience by enabling precise control of neural activity through light-sensitive proteins known as opsins. This review article discusses the fundamental principles of optogenetics, including the activation of both excitatory and inhibitory opsins, as well as the development of optogenetic models that utilize recombinant viral vectors. A considerable portion of the article addresses the limitations of optogenetic tools and explores strategies to overcome these challenges. These strategies include the use of adeno-associated viruses, cell-specific promoters, modified opsins, and methodologies such as bioluminescent optogenetics. The application of viral recombinant vectors, particularly adeno-associated viruses, is emerging as a promising avenue for clinical use in delivering opsins to target cells. This trend indicates the potential for creating tools that offer greater flexibility and accuracy in opsin delivery. The adaptations of these viral vectors provide advantages in optogenetic studies by allowing for the restricted expression of opsins through cellspecific promoters and various viral serotypes. The article also examines different cellular targets for optogenetics, including neurons, astrocytes, microglia, and Schwann cells. Utilizing specific promoters for opsin expression in these cells is essential for achieving precise and efficient stimulation. Research has demonstrated that optogenetic stimulation of both neurons and glial cells—particularly the distinct phenotypes of microglia, astrocytes, and Schwann cells—can have therapeutic effects in neurological diseases. Glial cells are increasingly recognized as important targets for the treatment of these disorders. Furthermore, the article emphasizes the emerging field of bioluminescent optogenetics, which combines optogenetic principles with bioluminescent proteins to visualize and manipulate neural activity in real time. By integrating molecular genetics techniques with bioluminescence, researchers have developed methods to monitor neuronal activity efficiently and less invasively, enhancing our understanding of central nervous system function and the mechanisms of plasticity in neurological disorders beyond traditional neurobiological methods. Evidence has shown that optogenetic modulation can enhance motor axon regeneration, achieve complete sensory reinnervation, and accelerate the recovery of neuromuscular function. This approach also induces complex patterns of coordinated motor neuron activity and promotes neural reorganization. Optogenetic approaches hold immense potential for therapeutic interventions in the central nervous system. They enable precise control of neural circuits and may offer new treatments for neurological disorders, particularly spinal cord injuries, peripheral nerve injuries, and other neurodegenerative diseases. Related Articles | Metrics

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Measuring glymphatic function: Assessing the toolkit Koushikk Ayyappan, Lucas Unger, Philip Kitchen, Roslyn M. Bill, Mootaz M. Salman 2026, 21 (2):  534-541.  doi: 10.4103/NRR.NRR-D-24-01013 Abstract ( 28 )   PDF (3202KB) ( 17 )   Save Glymphatic flow has been proposed to clear brain waste while we sleep. Cerebrospinal fluid moves from periarterial to perivenous spaces through the parenchyma, with subsequent cerebrospinal fluid drainage to dural lymphatics. Glymphatic disruption is associated with neurological conditions such as Alzheimer’s disease and traumatic brain injury. Therefore, investigating its structure and function may improve understanding of pathophysiology. The recent controversy on whether glymphatic flow increases or decreases during sleep demonstrates that the glymphatic hypothesis remains contentious. However, discrepancies between different studies could be due to limitations of the specific techniques used and confounding factors. Here, we review the methods used to study glymphatic function and provide a toolkit from which researchers can choose. We conclude that tracer analysis has been useful, ex vivo techniques are unreliable, and in vivo imaging is still limited. Finally, we explore the potential for future methods and highlight the need for in vitro models, such as microfluidic devices, which may address technique limitations and enable progression of the field. Related Articles | Metrics

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Innovative gene delivery systems for retinal disease therapy Hongguang Wu , Ling Dong , Shibo Jin, Yongwang Zhao , Lili Zhu 2026, 21 (2):  542-552.  doi: 10.4103/NRR.NRR-D-24-00797 Abstract ( 31 )   PDF (3329KB) ( 58 )   Save The human retina, a complex and highly specialized structure, includes multiple cell types that work synergistically to generate and transmit visual signals. However, genetic predisposition or age-related degeneration can lead to retinal damage that severely impairs vision or causes blindness. Treatment options for retinal diseases are limited, and there is an urgent need for innovative therapeutic strategies. Cell and gene therapies are promising because of the efficacy of delivery systems that transport therapeutic genes to targeted retinal cells. Gene delivery systems hold great promise for treating retinal diseases by enabling the targeted delivery of therapeutic genes to affected cells or by converting endogenous cells into functional ones to facilitate nerve regeneration, potentially restoring vision. This review focuses on two principal categories of gene delivery vectors used in the treatment of retinal diseases: viral and non-viral systems. Viral vectors, including lentiviruses and adeno-associated viruses, exploit the innate ability of viruses to infiltrate cells, which is followed by the introduction of therapeutic genetic material into target cells for gene correction. Lentiviruses can accommodate exogenous genes up to 8 kb in length, but their mechanism of integration into the host genome presents insertion mutation risks. Conversely, adeno-associated viruses are safer, as they exist as episomes in the nucleus, yet their limited packaging capacity constrains their application to a narrower spectrum of diseases, which necessitates the exploration of alternative delivery methods. In parallel, progress has also occurred in the development of novel non-viral delivery systems, particularly those based on liposomal technology. Manipulation of the ratios of hydrophilic and hydrophobic molecules within liposomes and the development of new lipid formulations have led to the creation of advanced non-viral vectors. These innovative systems include solid lipid nanoparticles, polymer nanoparticles, dendrimers, polymeric micelles, and polymeric nanoparticles. Compared with their viral counterparts, non-viral delivery systems offer markedly enhanced loading capacities that enable the direct delivery of nucleic acids, mRNA, or protein molecules into cells. This bypasses the need for DNA transcription and processing, which significantly enhances therapeutic efficiency. Nevertheless, the immunogenic potential and accumulation toxicity associated with nonviral particulate systems necessitates continued optimization to reduce adverse effects in vivo. This review explores the various delivery systems for retinal therapies and retinal nerve regeneration, and details the characteristics, advantages, limitations, and clinical applications of each vector type. By systematically outlining these factors, our goal is to guide the selection of the optimal delivery tool for a specific retinal disease, which will enhance treatment efficacy and improve patient outcomes while paving the way for more effective and targeted therapeutic interventions. Related Articles | Metrics

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Chemical exchange saturation transfer MRI for neurodegenerative diseases: An update on clinical and preclinical studies Ahelijiang Saiyisan, Shihao Zeng, Huabin Zhang, Ziyan Wang, Jiawen Wang, Pei Cai, Jianpan Huang 2026, 21 (2):  553-568.  doi: 10.4103/NRR.NRR-D-24-01246 Abstract ( 31 )   PDF (3214KB) ( 105 )   Save Chemical exchange saturation transfer magnetic resonance imaging is an advanced imaging technique that enables the detection of compounds at low concentrations with high sensitivity and spatial resolution and has been extensively studied for diagnosing malignancy and stroke. In recent years, the emerging exploration of chemical exchange saturation transfer magnetic resonance imaging for detecting pathological changes in neurodegenerative diseases has opened up new possibilities for early detection and repetitive scans without ionizing radiation. This review serves as an overview of chemical exchange saturation transfer magnetic resonance imaging with detailed information on contrast mechanisms and processing methods and summarizes recent developments in both clinical and preclinical studies of chemical exchange saturation transfer magnetic resonance imaging for Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and Huntington’s disease. A comprehensive literature search was conducted using databases such as PubMed and Google Scholar, focusing on peer-reviewed articles from the past 15 years relevant to clinical and preclinical applications. The findings suggest that chemical exchange saturation transfer magnetic resonance imaging has the potential to detect molecular changes and altered metabolism, which may aid in early diagnosis and assessment of the severity of neurodegenerative diseases. Although promising results have been observed in selected clinical and preclinical trials, further validations are needed to evaluate their clinical value. When combined with other imaging modalities and advanced analytical methods, chemical exchange saturation transfer magnetic resonance imaging shows potential as an in vivo biomarker, enhancing the understanding of neuropathological mechanisms in neurodegenerative diseases. Related Articles | Metrics

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Insights into the transcriptomic heterogeneity of brain endothelial cells in normal aging and Alzheimer’s disease Qian Yue, Shang Li, Chon Lok Lei, Huaibin Wan, Zaijun Zhang, Maggie Pui Man Hoi 2026, 21 (2):  569-576.  doi: 10.4103/NRR.NRR-D-24-00695 Abstract ( 43 )   PDF (2452KB) ( 22 )   Save Drug development for Alzheimer’s disease is extremely challenging, as demonstrated by the repeated failures of amyloid-β-targeted therapeutics and the controversies surrounding the amyloid-β cascade hypothesis. More recently, advances in the development of Lecanemab, an anti-amyloid-β monoclonal antibody, have shown positive results in reducing brain A burden and slowing cognitive decline in patients with early-stage Alzheimer’s disease in the Phase III clinical trial (Clarity Alzheimer’s disease). Despite these promising results, side effects such as amyloid-related imaging abnormalities (ARIA) may limit its usage. ARIA can manifest as ARIA-E (cerebral edema or effusions) and ARIA-H (microhemorrhages or superficial siderosis) and is thought to be caused by increased vascular permeability due to inflammatory responses, leading to leakages of blood products and protein-rich fluid into brain parenchyma. Endothelial dysfunction is an early pathological feature of Alzheimer’s disease, and the blood–brain barrier becomes increasingly leaky as the disease progresses. In addition, APOE4, the strongest genetic risk factor for Alzheimer’s disease, is associated with higher vascular amyloid burden, increased ARIA incidence, and accelerated blood–brain barrier disruptions. These interconnected vascular abnormalities highlight the importance of vascular contributions to the pathophysiology of Alzheimer’s disease. Here, we will closely examine recent research evaluating the heterogeneity of brain endothelial cells in the microvasculature of different brain regions and their relationships with Alzheimer’s disease progression. Related Articles | Metrics

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Recent advances in immunotherapy targeting amyloidbeta and tauopathies in Alzheimer’s disease Sha Sha, Lina Ren, Xiaona Xing, Wanshu Guo, Yan Wang, Ying Li, Yunpeng Cao, Le Qu 2026, 21 (2):  577-587.  doi: 10.4103/NRR.NRR-D-24-00846 Abstract ( 33 )   PDF (5739KB) ( 41 )   Save Alzheimer’s disease, a devastating neurodegenerative disorder, is characterized by progressive cognitive decline, primarily due to amyloid-beta protein deposition and tau protein phosphorylation. Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer’s disease. Conventional drugs, such as donepezil, can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline. Currently, active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer’s disease and other transgenic animal models, attracting considerable attention. However, the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab. This review first discusses the advancements in the pathogenesis of Alzheimer’s disease and active and passive immunotherapies targeting amyloid-beta and tau proteins. Furthermore, it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects. Although some antibodies have shown promise in patients with mild Alzheimer’s disease, substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer’s disease. Related Articles | Metrics

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Stress granules: Guardians of cellular health and triggers of disease Meghal Desai, Keya Gulati, Manasi Agrawal, Shruti Ghumra, Pabitra K. Sahoo 2026, 21 (2):  588-597.  doi: 10.4103/NRR.NRR-D-24-01196 Abstract ( 38 )   PDF (1639KB) ( 26 )   Save Stress granules are membraneless organelles that serve as a protective cellular response to external stressors by sequestering non-translating messenger RNAs (mRNAs) and regulating protein synthesis. Stress granules formation mechanism is conserved across species, from yeast to mammals, and they play a critical role in minimizing cellular damage during stress. Composed of heterogeneous ribonucleoprotein complexes, stress granules are enriched not only in mRNAs but also in noncoding RNAs and various proteins, including translation initiation factors and RNA-binding proteins. Genetic mutations affecting stress granule assembly and disassembly can lead to abnormal stress granule accumulation, contributing to the progression of several diseases. Recent research indicates that stress granule dynamics are pivotal in determining their physiological and pathological functions, with acute stress granule formation offering protection and chronic stress granule accumulation being detrimental. This review focuses on the multifaceted roles of stress granules under diverse physiological conditions, such as regulation of mRNA transport, mRNA translation, apoptosis, germ cell development, phase separation processes that govern stress granule formation, and their emerging implications in pathophysiological scenarios, such as viral infections, cancer, neurodevelopmental disorders, neurodegeneration, and neuronal trauma. Related Articles | Metrics

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Role of mitophagy in spinal cord ischemia-reperfusion injury Yanni Duan, Fengguang Yang, Yibao Zhang, Mingtao Zhang, Yujun Shi, Yun Lang, Hongli Sun, Xin Wang, Hongyun Jin, Xuewen Kang 2026, 21 (2):  598-611.  doi: 10.4103/NRR.NRR-D-24-00668 Abstract ( 37 )   PDF (1830KB) ( 28 )   Save Spinal cord ischemia-reperfusion injury, a severe form of spinal cord damage, can lead to sensory and motor dysfunction. This injury often occurs after traumatic events, spinal cord surgeries, or thoracoabdominal aortic surgeries. The unpredictable nature of this condition, combined with limited treatment options, poses a significant burden on patients, their families, and society. Spinal cord ischemia-reperfusion injury leads to reduced neuronal regenerative capacity and complex pathological processes. In contrast, mitophagy is crucial for degrading damaged mitochondria, thereby supporting neuronal metabolism and energy supply. However, while moderate mitophagy can be beneficial in the context of spinal cord ischemia-reperfusion injury, excessive mitophagy may be detrimental. Therefore, this review aims to investigate the potential mechanisms and regulators of mitophagy involved in the pathological processes of spinal cord ischemia-reperfusion injury. The goal is to provide a comprehensive understanding of recent advancements in mitophagy related to spinal cord ischemia-reperfusion injury and clarify its potential clinical applications. Related Articles | Metrics

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Neuronal guidance signaling in neurodegenerative diseases: Key regulators that function at neuron-glia and neuroimmune interfaces Junichi Yuasa-Kawada, Mariko Kinoshita-Kawada, Masaki Hiramoto, Satoru Yamagishi, Takayasu Mishima, Shin’ichiro Yasunaga, Yoshio Tsuboi, Nobutaka Hattori, Jane Y. Wu 2026, 21 (2):  612-635.  doi: 10.4103/NRR.NRR-D-24-01330 Abstract ( 28 )   PDF (4284KB) ( 45 )   Save The nervous system processes a vast amount of information, performing computations that underlie perception, cognition, and behavior. During development, neuronal guidance genes, which encode extracellular cues, their receptors, and downstream signal transducers, organize neural wiring to generate the complex architecture of the nervous system. It is now evident that many of these neuroguidance cues and their receptors are active during development and are also expressed in the adult nervous system. This suggests that neuronal guidance pathways are critical not only for neural wiring but also for ongoing function and maintenance of the mature nervous system. Supporting this view, these pathways continue to regulate synaptic connectivity, plasticity, and remodeling, and overall brain homeostasis throughout adulthood. Genetic and transcriptomic analyses have further revealed many neuronal guidance genes to be associated with a wide range of neurodegenerative and neuropsychiatric disorders. Although the precise mechanisms by which aberrant neuronal guidance signaling drives the pathogenesis of these diseases remain to be clarified, emerging evidence points to several common themes, including dysfunction in neurons, microglia, astrocytes, and endothelial cells, along with dysregulation of neuron-microglia-astrocyte, neuroimmune, and neurovascular interactions. In this review, we explore recent advances in understanding the molecular and cellular mechanisms by which aberrant neuronal guidance signaling contributes to disease pathogenesis through altered cell–cell interactions. For instance, recent studies have unveiled two distinct semaphorin-plexin signaling pathways that affect microglial activation and neuroinflammation. We discuss the challenges ahead, along with the therapeutic potentials of targeting neuronal guidance pathways for treating neurodegenerative diseases. Particular focus is placed on how neuronal guidance mechanisms control neuron-glia and neuroimmune interactions and modulate microglial function under physiological and pathological conditions. Specifically, we examine the crosstalk between neuronal guidance signaling and TREM2, a master regulator of microglial function, in the context of pathogenic protein aggregates. It is well-established that age is a major risk factor for neurodegeneration. Future research should address how aging and neuronal guidance signaling interact to influence an individual’s susceptibility to various late-onset neurological diseases and how the progression of these diseases could be therapeutically blocked by targeting neuronal guidance pathways. Related Articles | Metrics

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Novel insights into non-coding RNAs and their role in hydrocephalus Zhiyue Cui, Jian He, An Li, Junqiang Wang, Yijian Yang, Kaiyue Wang, Zhikun Liu, Qian Ouyang, Zhangjie Su, Pingsheng Hu, Gelei Xiao 2026, 21 (2):  636-647.  doi: 10.4103/NRR.NRR-D-24-00963 Abstract ( 27 )   PDF (2340KB) ( 33 )   Save A large body of evidence has highlighted the role of non-coding RNAs in neurodevelopment and neuroinflammation. This evidence has led to increasing speculation that non-coding RNAs may be involved in the pathophysiological mechanisms underlying hydrocephalus, one of the most common neurological conditions worldwide. In this review, we first outline the basic concepts and incidence of hydrocephalus along with the limitations of existing treatments for this condition. Then, we outline the definition, classification, and biological role of non-coding RNAs. Subsequently, we analyze the roles of non-coding RNAs in the formation of hydrocephalus in detail. Specifically, we have focused on the potential significance of non-coding RNAs in the pathophysiology of hydrocephalus, including glymphatic pathways, neuroinflammatory processes, and neurological dysplasia, on the basis of the existing evidence. Lastly, we review the potential of non-coding RNAs as biomarkers of hydrocephalus and for the creation of innovative treatments. Related Articles | Metrics

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Is age-related myelinodegenerative change an initial risk factor of neurodegenerative diseases? Shuangchan Wu, Jun Chen 2026, 21 (2):  648-658.  doi: 10.4103/NRR.NRR-D-24-00848 Abstract ( 52 )   PDF (2781KB) ( 50 )   Save Myelination, the continuous ensheathment of neuronal axons, is a lifelong process in the nervous system that is essential for the precise, temporospatial conduction of action potentials between neurons. Myelin also provides intercellular metabolic support to axons. Even minor disruptions in the integrity of myelin can impair neural performance and increase susceptibility to neurological diseases. In fact, myelin degeneration is a well-known neuropathological condition that is associated with normal aging and several neurodegenerative diseases, including multiple sclerosis and Alzheimer’s disease. In the central nervous system, compact myelin sheaths are formed by fully mature oligodendrocytes. However, the entire oligodendrocyte lineage is susceptible to changes in the biological microenvironment and other risk factors that arise as the brain ages. In addition to their well-known role in action potential propagation, oligodendrocytes also provide intercellular metabolic support to axons by transferring energy metabolites and delivering exosomes. Therefore, myelin degeneration in the aging central nervous system is a significant contributor to the development of neurodegenerative diseases. Interventions that mitigate age-related myelin degeneration can improve neurological function in aging individuals. In this review, we investigate the changes in myelin that are associated with aging and their underlying mechanisms. We also discuss recent advances in understanding how myelin degeneration in the aging brain contributes to neurodegenerative diseases and explore the factors that can prevent, slow down, or even reverse age-related myelin degeneration. Future research will enhance our understanding of how reducing age-related myelin degeneration can be used as a therapeutic target for delaying or preventing neurodegenerative diseases. Related Articles | Metrics

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Intersection of mitochondrial dysfunction and myelination: An overlooked aspect in neurodevelopmental disorders Ariel Nir Sade, Gal Wiener, Boaz Barak 2026, 21 (2):  659-660.  doi: 10.4103/NRR.NRR-D-24-01025 Abstract ( 28 )   PDF (1291KB) ( 10 )   Save Neurodevelopmental processes represent a finely tuned interplay between genetic and environmental factors, shaping the dynamic landscape of the developing brain. A major component of the developing brain that enables this dynamic is the white matter (WM), known to be affected in neurodevelopmental disorders (NDDs) (Rokach et al., 2024). WM formation is mediated by myelination, a multifactorial process driven by neuro-glia interactions dependent on proper neuronal functionality (Simons and Trajkovic, 2006). Another key aspect of neurodevelopmental abnormalities involves neuronal dynamics and function, with recent advances significantly enhancing our understanding of both neuronal and glial mitochondrial function (Devine and Kittler, 2018; Rojas-Charry et al., 2021). Energy homeostasis in neurons, attributed largely to mitochondrial function, is critical for proper functionality and interactions with oligodendrocytes (OLs), the cells forming myelin in the brain’s WM. We herein discuss the interplay between these processes and speculate on potential dysfunction in NDDs. Related Articles | Metrics

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Polysialic acid-Siglec immune checkpoints of microglia and macrophages: Perspectives for therapeutic intervention Hauke Thiesler, Herbert Hildebrandt 2026, 21 (2):  661-662.  doi: 10.4103/NRR.NRR-D-24-01195 Abstract ( 28 )   PDF (3053KB) ( 9 )   Save Microglia are the resident macrophages of the central nervous system. They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neurodegenerative and demyelinating diseases (Borst et al., 2021). Together with infiltrating monocytederived macrophages, microglia also play a critical role for brain tumor development, since immunosuppressive interactions between tumor cells and tumor-associated microglia and macrophages (TAM) are linked to malignant progression. This mechanism is of particular relevance in glioblastoma (GB), the deadliest form of brain cancer with a median overall survival of less than 15 months (Khan et al., 2023). Therefore, targeting microglia and macrophage activation is a promising strategy for therapeutic interference in brain disease. Related Articles | Metrics

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FIREproof: Intricacies of microglial biology Wei Cao 2026, 21 (2):  663-664.  doi: 10.4103/NRR.NRR-D-24-01198 Abstract ( 30 )   PDF (470KB) ( 14 )   Save Microglia are the macrophages that populate the brain parenchyma. Research in the past decades has identified them as both essential guardians of the brain and significant contributors to various neurological diseases. A highly versatile cell type, microglia have been shown to fulfill a multitude of critical roles in the central nervous system, including facilitating neurogenesis and myelination, pruning synapses, removing debris and waste, modulating neuronal activity, supporting the blood–brain barrier, repairing tissue damage, and surveilling against microbial invasions under physiological conditions (Prinz et al., 2021; Paolicelli et al., 2022). Yet, recent studies on fms intronic regulatory element (FIRE) mice (Rojo et al., 2019), an engineered rodent strain completely devoid of microglia, have considerably altered our perceptions of these cells’ influence on brain homeostasis. Contrary to earlier beliefs, microglia are largely dispensable for neurogenesis, synaptogenesis, oligodendrocyte maturation, and vasculature formation (Rojo et al., 2019; McNamara et al., 2023; Profaci et al., 2024; Surala et al., 2024). However, they are essential for maintaining myelin health, safeguarding structural integrity during the development of central nervous system, and protecting against ageassociated brain pathologies (McNamara et al., 2023; Chadarevian et al., 2024; Lawrence et al., 2024; Munro et al., 2024). These findings provide invaluable insights into the pathogenesis of adultonset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) (Prinz et al., 2021; Paolicelli et al., 2022), a rare neurodegenerative disorder affected by microgliopathy, while also highlighting potential therapeutic strategies. As research continues to unravel the intricacies of microglial biology, it promises to further advance our understanding and facilitate clinical translation in the future. Related Articles | Metrics

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Specific dendritic spine modifications and dendritic transport: From in vitro to in vivo Albert H.K. Fok, Charlotte H.M. Lam, Cora S.W. Lai 2026, 21 (2):  665-666.  doi: 10.4103/NRR.NRR-D-24-01159 Abstract ( 29 )   PDF (2279KB) ( 9 )   Save Dendritic spines are small protrusions along dendrites that contain most of the excitatory synapses in principal neurons, playing a crucial role in neuronal function by creating a compartmentalized environment for signal transduction. The plasticity of spine morphologies provides a tunable handle to regulate calcium signal dynamics, allowing rapid regulation of protein expression necessary to establish and maintain synapses (Cornejo et al., 2022). If excitatory inputs were to be located primarily on dendritic shafts, dendrites would frequently short-circuit, preventing voltage signals from propagating (Cornejo et al., 2022). It is thus not surprising that the structural plasticity of dendritic spines is closely linked to synaptic plasticity and memory formation (Berry and Nedivi, 2017). While comprehensive in vitro studies have been conducted, in vivo studies that directly tackle the mechanism of dendritic transport and translation in regulating spine plasticity spatiotemporally are limited. Related Articles | Metrics

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Unraveling the role of ufmylation in the brain Rita J. Serrano, Robert J. Bryson-Richardson 2026, 21 (2):  667-668.  doi: 10.4103/NRR.NRR-D-24-01311 Abstract ( 35 )   PDF (1606KB) ( 15 )   Save Ufmylation is an ubiquitin-like post-translational modification characterized by the covalent binding of mature UFM1 to target proteins. Although the consequences of ufmylation on target proteins are not fully understood, its importance is evident from the disorders resulting from its dysfunction. Numerous case reports have established a link between biallelic loss-of-function and/or hypomorphic variants in ufmylation-related genes and a spectrum of pediatric neurodevelopmental disorders. These include developmental and epileptic encephalopathy (DEE44), autosomal r e c e s s i v e c e r e b e l l a r a t a x i a , c o n g e n i t a l neuropathy, hypomyelinating leukodystrophy, and neurodevelopmental disorder with spasticity and poor growth, each presenting with varying severity (Zhou et al., 2024). Children affected by these disorders often exhibit a range of symptoms, including intellectual disability, seizures, microcephaly, abnormal electroencephalogram, impaired motor function, dystonia, and/or global developmental delay, which result in premature death in severe cases. Variants in ufmylation genes have been shown to disrupt UFM1 activation and/or transthiolation, thereby impairing the ufmylation pathway (Pan et al., 2023; Zhou et al., 2024). These findings underline the importance of maintaining balanced ufmylation activity for optimal brain development and function. Related Articles | Metrics

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ABCA5 lipid transporter is associated with a reduced risk of Parkinson’s disease Jasmin Galper, Nicolas Dzamko, Woojin Scott Kim 2026, 21 (2):  669-670.  doi: 10.4103/NRR.NRR-D-24-01031 Abstract ( 38 )   PDF (507KB) ( 11 )   Save A key pathological feature of Parkinson’s disease (PD) is that lysosomes are overwhelmed with cellular materials that need to be degraded and cleared. While the build-up of protein is characteristic of neurodegenerative diseases such as PD and Alzheimer’s disease (AD) and is thought to reflect lysosome dysfunction, lipid accumulation may also contribute to and be indicative of severe lysosomal dysfunction. Much is known about the detrimental effects of glucosylceramide accumulation in PD lysosomes. In fact, the most common genetic risk factor for PD is GBA1, which converts glucosylceramide to ceramide. Gaucher’s disease, which has a genetic overlap with PD, is a classic example of the toxic build-up of lysosomal lipids being associated with a neurodegenerative condition. The removal of diverse lipids, including sterols and sphingolipids from lysosomes and cells, occurs through the actions of a group of proteins known as ATP Binding Cassette subfamily A (ABCA) transporters (Lok et al., 2024). Results from a genome-wide association study indicate that ABCA5 single nucleotide polymorphisms were associated with a reduced risk of PD (SimónSánchez et al., 2009), prompting further research into ABCA5 function. A recent study has indicated that the levels of the PD pathological hallmark protein α-synuclein are affected by sphingomyelin efflux via the ABCA5 transporter and highlights a new avenue for alleviating the lysosomal burden and α-synuclein levels in PD (Fu et al., 2024). Related Articles | Metrics

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Sesquiterpene lactones as potential drugs treating nerve injury Philipp Gobrecht, Marco Leibinger, Dietmar Fischer 2026, 21 (2):  671-672.  doi: 10.4103/NRR.NRR-D-24-00735 Abstract ( 32 )   PDF (606KB) ( 13 )   Save Traumatic axonal lesions of peripheral nerves disrupt neuronal connections with their targets, resulting in the loss of motor and sensory functions. Despite the peripheral nervous system’s capacity for axonal regrowth, this may lead to permanent impairements resulting in a loss of quality of life and a high socioeconomic burden. For example, peripheral nerve injuries in the upper extremities are relatively common, especially due to work-related accidents, and can lead to significant morbidity and long-term costs. A study found that 30% of patients with work-related nerve injuries experienced permanent disabilities, requiring financial compensation and impacting their quality of life. The estimated lifetime cost per patient with severe injury, including treatment, rehabilitation, and compensation, is approximately €102,167, highlighting the substantial economic impact of these injuries (Bergmeister et al., 2020). Related Articles | Metrics

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Stress signaling caused by mitochondrial import malfunction can be terminated by SIFI: Importance of stress response silencing Grace Hohman, Michael Shahid, Mohamed A. Eldeeb 2026, 21 (2):  673-674.  doi: 10.4103/NRR.NRR-D-24-01169 Abstract ( 36 )   PDF (1248KB) ( 15 )   Save Protein aggregates, mitochondrial import stress and neurodegenerative disorders: A salient hallmark of several neurodegenerative diseases, including Parkinson’s disease, is the abundance of protein aggregates (Goiran et al., 2022). This molecular event is believed to lead to activation of stress pathways ultimately resulting in cellular dysfunction (Eldeeb et al., 2022). Accordingly, many lines of research investigations focused on dampening the formation of protein aggregates or augmenting the clearance of protein aggregates as a potential therapeutic strategy to counteract the progression of neurodegenerative diseases, albeit with little success (Costa-Mattioli and Walter, 2020). Cell stress cues such as the accumulation of protein aggregates lead to the activation of stress response pathways that aid cells in responding to the damage. Despite the notion that the transient activation of these pathways helps cells cope with stressors, persistent activation can induce unwanted apoptosis of cells and reduce overall tissue strength as well as lead to an accumulation of aggregationprone proteins (Hetz and Papa, 2018). Mutations in proteins involved in stress signaling termination can cause conditions like ataxia and early-onset dementia (Conroy et al., 2014). Therefore, it is crucial for stress response signaling to be turned off once conditions have improved. Nevertheless, the mechanisms by which cells silence these signals are still elusive. Related Articles | Metrics

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p21 as an essential regulator of neurogenic homeostasis in neuropathological conditions Valentina Mastrorilli, Stefano Farioli-Vecchioli 2026, 21 (2):  675-676.  doi: 10.4103/NRR.NRR-D-24-01255 Abstract ( 29 )   PDF (1595KB) ( 5 )   Save Adult neurogenesis is a highly dynamic process that leads to the production of new neurons from a population of quiescent neural stem cells (NSCs). In response to specific endogenous and/or external stimuli, NSCs enter a state of mitotic activation, initiating proliferation and differentiation pathways. Throughout this process, NSCs give rise to neural progenitors, which undergo multiple replicative and differentiative steps, each governed by precise molecular pathways that coordinate cellular changes and signals from the surrounding neurogenic niche. The ultimate goal of this complex genetic machinery is to ensure a continuous supply of new mature and functionally active neurons to pre-existing neural circuits, while also maintaining the neural stem cell pool as intact as possible, both under physiological conditions and in response to positive or negative external stimuli (Niklison-Chirou et al., 2020). In fact, disruption of this delicate balance can lead to neurogenic deficits or depletion of the NSCs pool. In this context, p21 has been identified as a key regulator of two pivotal processes in adult neurogenesis: the transition between quiescence and activation of NSCs, and the progression of progenitor proliferation (Maeda et al. 2023). Related Articles | Metrics

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Utilizing Single-cell and Spatial RNAseq databasE for Alzheimer’s Disease (ssREAD) in hypothesis-driven queries Diana Acosta, Cankun Wang, Qin Ma , Hongjun Fu 2026, 21 (2):  677-678.  doi: 10.4103/NRR.NRR-D-24-01201 Abstract ( 41 )   PDF (875KB) ( 14 )   Save Alzheimer’s disease (AD) is the most common form of dementia. In addition to the lack of effective treatments, there are limitations in diagnostic capabilities. The complexity of AD itself, together with a variety of other diseases often observed in a patient’s history in addition to their AD diagnosis, make deciphering the molecular mechanisms that underlie AD, even more important. Large datasets of single-cell RNA sequencing, singlenucleus RNA-sequencing (snRNA-seq), and spatial transcriptomics (ST) have become essential in guiding and supporting new investigations into the cellular and regional susceptibility of AD. However, with unique technology, software, and larger databases emerging; a lack of integration of these data can contribute to ineffective use of valuable knowledge. Importantly, there was no specialized database that concentrates on ST in AD that offers comprehensive differential analyses under various conditions, such as sex-specific, region-specific, and comparisons between AD and control groups until the new Single-cell and Spatial RNA-seq databasE for Alzheimer’s Disease (ssREAD) database (Wang et al., 2024) was introduced to meet the scientific community’s growing demand for comprehensive, integrated, and accessible data analysis. Related Articles | Metrics

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Mitochondria-derived vesicles: New players in the game of neurodegeneration Laura Palumbo , Domenico Nuzzo , Antonella Girgenti, Pasquale Picone 2026, 21 (2):  679-680.  doi: 10.4103/NRR.NRR-D-24-01220 Abstract ( 45 )   PDF (1252KB) ( 6 )   Save Introduction: One of the main events that regulate a cell’s well-being is cell-to-cell communication. This intercellular mechanism of information transfer is often mediated by vesicular trafficking. Mitochondrial-derived vesicles (MDVs) are an emerging subpopulation of extracellular vesicle (EV) first discovered in 2008 that allow mitochondria to communicate with their surroundings. The principal information and characteristics of these vesicles are proficiently discussed and summarized in a recent work published by Hazan Ben-Menachem et al. (2024). MDVs are vesicles ranging in size from 70 nm to 150 nm, originating from mitochondrial subcompartments and released into the cytosol. Depending on their biogenesis mechanism, they may present a single outer membrane or both an outer membrane and an inner membrane. Furthermore, they carry matrix proteins and oxidative phosphorylation system components (Hazan Ben-Menachem et al., 2024). These vesicles are capable of interacting with various intracellular organelles as well as the extracellular environment, producing EVs. This enables them to perform a dual role of transmitting intracellular signals and transporting mitochondrial components outside the cell. Accordingly, these vesicles remove damaged mitochondrial components, preserve mitochondrial structural and functional integrity, and restore proper homeostasis, thereby fulfilling a key role in mitochondrial quality control (Hazan Ben-Menachem et al., 2024). The formation of these MDVs is a housekeeping process that occurs physiologically in functionally active mitochondria. However, under pathological stress conditions, such as nutrient deprivation or exposure to toxins, and mitochondrial oxidative stress, their generation increases to remove damaged mitochondrial components. Interestingly, this process is beneficial for the cell and, although it shares several similarities, it is dissociated from mitophagy, which occurs later and only when the mitochondrion is severely damaged. Supporting this, MDV formation does not require autophagic machinery. Once assembled, the vesicles transporting mitochondria-damaged components move towards peroxisomes or lysosomes for degradation (Figure 1). Related Articles | Metrics

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Amyloid-β is NOT only the most promising target for Alzheimer’s disease Beka Solomon , Milana Voronov-Goldman 2026, 21 (2):  681-682.  doi: 10.4103/NRR.NRR-D-24-00829 Abstract ( 32 )   PDF (675KB) ( 8 )   Save Amyloid-β (Aβ) and tau, the two hallmark proteins associated with Alzheimer’s disease (AD), exhibit distinct toxic effects but also interact synergistically within the disease pathology. The prevailing theory in AD pathology—the amyloid cascade hypothesis—highlights the pivotal role of increased processing of the amyloid precursor protein (APP). Initially cleaved by the major β-secretase (β-amyloid cleaving enzyme-1, BACE1) in the brain, then undergoes further cleavage by the γ-secretase complex, resulting in the production of Aβ40–42 and a set of intracellular C-terminal peptides known as Aβ and APP intracellular domain (β-AICDs) and soluble amyloid precursor protein β (sAPPβ) (Orobets and Karamyshev, 2023). Related Articles | Metrics

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Biomarkers for synaptic dysfunction in Alzheimer’s disease Ruiqing Ni 2026, 21 (2):  683-684.  doi: 10.4103/NRR.NRR-D-24-01227 Abstract ( 30 )   PDF (531KB) ( 15 )   Save Alzheimer’s disease (AD) is the most common cause of dementia, characterized by progressive cognitive decline, and affects over 55 million people worldwide. AD is pathological featured by the aberrant accumulation of amyloid-β plaques, neurofibrillary tangles formed by hyperphosphorylated tau, synaptic loss, and dysfunction of neurotransmitter systems. Evidence from in vivo and autopsy studies has consistently shown that synaptic dysfunction and loss are strongly correlated with cognitive decline in AD, particularly in brain regions such as the hippocampus and cortex, which are critical for memory formation and processing. This perspective highlights recent histopathological findings related to synaptic dysfunction in AD, advancements in the development of imaging and fluid-based biomarkers for synaptic loss, and future studies. Related Articles | Metrics

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Rapamycin as a preventive intervention for Alzheimer’s disease in APOE4 carriers: Targeting brain metabolic and vascular restoration Ai-Ling Lin , Chetan Aware 2026, 21 (2):  685-686.  doi: 10.4103/NRR.NRR-D-24-01006 Abstract ( 36 )   PDF (6103KB) ( 10 )   Save Alzheimer ’s disease (AD) is the most common form of dementia, affecting over 50 million people worldwide. This figure is projected to nearly double every 20 years, reaching 82 million by 2030 and 152 million by 2050 (Alzheimer’s Disease International). The apolipoprotein ε4 (APOE4) allele is the strongest genetic risk factor for late-onset AD (after age 65 years). Apolipoprotein E, a lipid transporter, exists in three variants: ε2, ε3, and ε4. APOE ε2 (APOE2) is protective against AD, APOE ε3 (APOE3) is neutral, while APOE4 significantly increases the risk. Individuals with one copy of APOE4 have a 4-fold greater risk of developing AD, and those with two copies face an 8-fold risk compared to non-carriers. Even in cognitively normal individuals, APOE4 carriers exhibit brain metabolic and vascular deficits decades before amyloid-beta (Aβ) plaques and neurofibrillary tau tangles emerge—the hallmark pathologies of AD (Reiman et al., 2001, 2005; Thambisetty et al., 2010). Notably, studies have demonstrated reduced glucose uptake, or hypometabolism, in brain regions vulnerable to AD in asymptomatic middle-aged APOE4 carriers, long before clinical symptoms arise (Reiman et al., 2001, 2005). Related Articles | Metrics

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Towards mechanism-based tautargeted therapies Lidia Bakota, Roland Brandt 2026, 21 (2):  687-688.  doi: 10.4103/NRR.NRR-D-24-01240 Abstract ( 22 )   PDF (811KB) ( 9 )   Save T a u p l a y s a c r u c i a l r o l e i n s e v e r a l neurodegenerative diseases, collectively referred to as tauopathies. Therefore, targeting potential pathological changes in tau could enable useful therapeutic interventions. However, tau is not an easy target because it dynamically interacts with microtubules and other cellular components, which presents a challenge for tau-targeted drugs. New cellular models could aid the development of mechanism-based tau-targeted therapies. Related Articles | Metrics

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Human stem cell–based cell replacement therapy for Parkinson’s disease: Enhancing the survival of postmitotic dopamine neuron grafts Tae Wan Kim 2026, 21 (2):  689-690.  doi: 10.4103/NRR.NRR-D-24-01394 Abstract ( 23 )   PDF (1592KB) ( 7 )   Save Parkinson’s disease (PD) is the second most common neurodegenerative disorder. The progressive degeneration of dopamine (DA) producing neurons in the midbrain is the pathological hallmark, which leads to debilitating motor symptoms, including tremors, rigidity, and bradykinesia. Drug treatments, such as levodopa, provide symptomatic relief. However, they do not halt disease progression, and their effectiveness diminishes over time (reviewed in Poewe et al., 2017). One of the most promising therapeutic strategies for PD is cell-based replacement therapy, particularly using human pluripotent stem cells (hPSCs), which are thought to be capable of restoring dopaminergic function at cellular and circuit levels (Kim et al., 2020). Given the extensive preclinical studies showing the immense translational potential of hPSC-based therapies in PD, recent reports indicate that cell replacement therapy using hPSC-derived DA cells has progressed from the preclinical phase to actual clinical trials in PD patients (Kikuchi et al., 2017; Schweitzer et al., 2020; Kim et al., 2021; Kirkeby et al., 2023). Related Articles | Metrics

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Liquid biopsies in psychiatric disorders: Identifying peripheral biomarkers of brain health Jennifer L. Payne, Sarven Sabunciyan 2026, 21 (2):  691-692.  doi: 10.4103/NRR.NRR-D-24-00962 Abstract ( 21 )   PDF (634KB) ( 23 )   Save The inability to access brain tissue has greatly hindered our ability to study and care for individuals suffering from psychiatric and neurological conditions. Critics have questioned efforts to develop peripheral blood biomarkers in neurological and psychiatric disorders based on the assertion that disease pathology is limited to the brain. The discovery that all tissues, including the brain, release extracellular vesicles (Raposo and Stoorvogel, 2013) and cell free DNAs (Chan et al., 2013) into various body fluids has provided a potential way to measure activity from inaccessible tissues like the central nervous system (CNS) and has given rise to the term “liquid biopsy.” The development of liquid biopsies that can diagnose and predict the course of psychiatric and neurological disorders would be transformative. The ability to predict episodic events such as mania, depression, and risk for suicide would be particularly useful for psychiatric care as it would enable the development of interventions that prevent mortality and improve outcomes. Additionally, biomarkers that are informative about drug response and aid in treatment decisions would be a significant advance in psychiatric care as it would prevent patients from having to endure multiple courses of ineffective treatments and side effects. Related Articles | Metrics

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Targeting Wallerian degeneration in glaucoma Melissa Jöe, Pete A. Williams 2026, 21 (2):  693-694.  doi: 10.4103/NRR.NRR-D-24-01160 Abstract ( 24 )   PDF (674KB) ( 11 )   Save Neurodegenerative diseases account for a large and increasing health and economic burden worldwide. With an increasingly aged population, this burden is set to increase. Optic neuropathies make up a large proportion of neurodegenerative diseases with glaucoma being highly prevalent. Glaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells and their axons which make up the optic nerve. It is the leading cause of irreversible vision loss and affects an estimated 80 million people. The mammalian central nervous system is non-regenerative and, once lost or injured, retinal ganglion cells cannot regenerate an axon into the optic nerve under basal conditions. Thus, strategies that provide neuroprotection to stressed, dysfunctional, or dying retinal ganglion cells are likely to be of high therapeutic and translational value. Advancing age, genetics, and elevated intraocular pressure are all major risk factors for glaucoma, however, all clinically available glaucoma treatments focus on intraocular pressure management and do not directly address the neurodegenerative component of glaucoma. Related Articles | Metrics

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Grafts of hydrogel-embedded electrically stimulated subventricular stem cells into the stroke cavity improves functional recovery of mice Andreea-Mihaela Cercel, Ianis KS Boboc, Roxana Surugiu, Thorsten R. Doeppner, Dirk M. Hermann, Bogdan Catalin, Andrei Gresita, Aurel Popa-Wagner 2026, 21 (2):  695-703.  doi: 10.4103/NRR.NRR-D-23-02092 Abstract ( 34 )   PDF (6302KB) ( 24 )   Save The major aim of stroke therapy is to stimulate brain repair and improve behavioral recovery after cerebral ischemia. One option is to stimulate endogenous neurogenesis in the subventricular zone and direct the newly formed neurons to the damaged area. However, only a small percentage of these neurons survive, and many do not reach the damaged area, possibly because the corpus callosum impedes the migration of subventricular zone-derived stem cells into the lesioned cortex. A second major obstacle to stem cell therapy is the strong inflammatory reaction induced by cerebral ischemia, whereby the associated phagocytic activity of brain macrophages removes both therapeutic cells and/or cell-based drug carriers. To address these issues, neurogenesis was electrically stimulated in the subventricular zone, followed by isolation of proliferating cells, including newly formed neurons, which were subsequently mixed with a nutritional hydrogel. This mixture was then transferred to the stroke cavity of day 14 post-stroke mice. We found that the performance of the treated animals improved in behavioral tests, including novel object, open field, hole board, grooming, and “time-to-feel” adhesive tape tests. Furthermore, immunostaining revealed that the stem cell marker nestin, the neuroepithelial marker Mash1, and the immature neuronal marker doublecortin-positive cells survived in the transplanted area for 2 weeks, possibly due to reduced phagocytic activity and supportive angiogenesis. These results clearly indicate that the transplantation of committed subventricular zone stem cells combined with a protective nutritional gel directly into the infarct cavity after the peak of stroke-induced neuroinflammation represents a feasible approach to improve neurorestoration after cerebral ischemia. Related Articles | Metrics

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Tropism-shifted AAV-PHP.eB-mediated bFGF gene therapy promotes varied neurorestoration after ischemic stroke in mice Rubing Shi, Jing Ye, Ze Liu, Cheng Wang, Shengju Wu, Hui Shen, Qian Suo, Wanlu Li, Xiaosong He, Zhijun Zhang, Yaohui Tang, Guo-Yuan Yang, Yongting Wang 2026, 21 (2):  704-714.  doi: 10.4103/NRR.NRR-D-23-01802 Abstract ( 87 )   PDF (5514KB) ( 68 )   Save AAV-PHP.eB is an artificial adeno-associated virus (AAV) that crosses the blood–brain barrier and targets neurons more efficiently than other AAVs when administered systematically. While AAV-PHP.eB has been used in various disease models, its cellular tropism in cerebrovascular diseases remains unclear. In the present study, we aimed to elucidate the tropism of AAV-PHP.eB for different cell types in the brain in a mouse model of ischemic stroke and evaluate its effectiveness in mediating basic fibroblast growth factor (bFGF) gene therapy. Mice were injected intravenously with AAV-PHP.eB either 14 days prior to (prestroke) or 1 day following (post-stroke) transient middle cerebral artery occlusion. Notably, we observed a shift in tropism from neurons to endothelial cells with post-stroke administration of AAV-PHP.eB-mNeonGreen (mNG). This endothelial cell tropism correlated strongly with expression of the endothelial membrane receptor lymphocyte antigen 6 family member A (Ly6A). Furthermore, AAV-PHP.eB-mediated overexpression of bFGF markedly improved neurobehavioral outcomes and promoted long-term neurogenesis and angiogenesis post–ischemic stroke. Our findings underscore the significance of considering potential tropism shifts when utilizing AAV-PHP.eB-mediated gene therapy in neurological diseases and suggest a promising new strategy for bFGF gene therapy in stroke treatment. Related Articles | Metrics

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Bromodomain-containing protein 4 knockdown promotes neuronal ferroptosis in a mouse model of subarachnoid hemorrhage Peng Lu, Fan Zhang, Lei Yang, Yijing He, Xi Kong, Kecheng Guo, Yuke Xie, Huangfan Xie, Bingqing Xie, Yong Jiang, Jianhua Peng 2026, 21 (2):  715-729.  doi: 10.4103/NRR.NRR-D-24-00147 Abstract ( 39 )   PDF (14560KB) ( 4 )   Save Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage. Neuronal ferroptosis in particular plays an important role in early brain injury. Bromodomain-containing protein 4, a member of the bromo and extraterminal domain family of proteins, participated in multiple cell death pathways, but the mechanisms by which it regulates ferroptosis remain unclear. The primary aim of this study was to investigate how bromodomain-containing protein 4 affects neuronal ferroptosis following subarachnoid hemorrhage in vivo and in vitro. Our findings revealed that endogenous bromodomain-containing protein 4 co-localized with neurons, and its expression was decreased 48 hours after subarachnoid hemorrhage of the cerebral cortex in vivo. In addition, ferroptosis-related pathways were activated in vivo and in vitro after subarachnoid hemorrhage. Targeted inhibition of bromodomain-containing protein 4 in neurons increased lipid peroxidation and intracellular ferrous iron accumulation via ferritinophagy and ultimately led to neuronal ferroptosis. Using cleavage under targets and tagmentation analysis, we found that bromodomain-containing protein 4 enrichment in the Raf-1 promoter region decreased following oxyhemoglobin stimulation in vitro. Furthermore, treating bromodomain-containing protein 4-knockdown HT-22 cell lines with GW5074, a Raf-1 inhibitor, exacerbated neuronal ferroptosis by suppressing the Raf-1/ERK1/2 signaling pathway. Moreover, targeted inhibition of neuronal bromodomain-containing protein 4 exacerbated early and long-term neurological function deficits after subarachnoid hemorrhage. Our findings suggest that bromodomain-containing protein 4 may have neuroprotective effects after subarachnoid hemorrhage, and that inhibiting ferroptosis could help treat subarachnoid hemorrhage. Related Articles | Metrics

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Fat mass and obesity–mediated N6 -methyladenosine modification modulates neuroinflammatory responses after traumatic brain injury Xiangrong Chen, Jinqing Lai, Zhe Wu, Jianlong Chen, Baoya Yang, Chunnuan Chen, Chenyu Ding 2026, 21 (2):  730-741.  doi: 10.4103/NRR.NRR-D-23-01854 Abstract ( 39 )   PDF (5486KB) ( 20 )   Save The neuroinflammatory response mediated by microglial activation plays an important role in the secondary nerve injury of traumatic brain injury. The posttranscriptional modification of N6 -methyladenosine is ubiquitous in the immune response of the central nervous system. The fat mass and obesity-related protein catalyzes the demethylation of N6 -methyladenosine modifications on mRNA and is widely expressed in various tissues, participating in the regulation of multiple diseases’ biological processes. However, the role of fat mass and obesity in microglial activation and the subsequent neuroinflammatory response after traumatic brain injury is unclear. In this study, we found that the expression of fat mass and obesity was significantly down-regulated in both lipopolysaccharidetreated BV2 cells and a traumatic brain injury mouse model. After fat mass and obesity interference, BV2 cells exhibited a pro-inflammatory phenotype as shown by the increased proportion of CD11b+ /CD86+ cells and the secretion of pro-inflammatory cytokines. Fat mass and obesity-mediated N6 -methyladenosine demethylation accelerated the degradation of ADAM17 mRNA, while silencing of fat mass and obesity enhanced the stability of ADAM17 mRNA. Therefore, down-regulation of fat mass and obesity expression leads to the abnormally high expression of ADAM17 in microglia. These results indicate that the activation of microglia and neuroinflammatory response regulated by fat mass and obesity-related N6 -methyladenosine modification plays an important role in the proinflammatory process of secondary injury following traumatic brain injury. Related Articles | Metrics

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Blood–brain barrier disruption and neuroinflammation in the hippocampus of a cardiac arrest porcine model: Single-cell RNA sequencing analysis Tangxing Jiang, Yaning Li, Hehui Liu, Yijun Sun, Huidan Zhang, Qirui Zhang, Shuyao Tang, Xu Niu, Han Du, Yinxia Yu, Hongwei Yue, Yunyun Guo, Yuguo Chen, Feng Xu 2026, 21 (2):  742-755.  doi: 10.4103/NRR.NRR-D-24-01269 Abstract ( 50 )   PDF (52915KB) ( 6 )   Save Global brain ischemia and neurological deficit are consequences of cardiac arrest that lead to high mortality. Despite advancements in resuscitation science, our limited understanding of the cellular and molecular mechanisms underlying post-cardiac arrest brain injury have hindered the development of effective neuroprotective strategies. Previous studies primarily focused on neuronal death, potentially overlooking the contributions of non-neuronal cells and intercellular communication to the pathophysiology of cardiac arrest-induced brain injury. To address these gaps, we hypothesized that single-cell transcriptomic analysis could uncover previously unidentified cellular subpopulations, altered cell communication networks, and novel molecular mechanisms involved in post–cardiac arrest brain injury. In this study, we performed a single-cell transcriptomic analysis of the hippocampus from pigs with ventricular fibrillation-induced cardiac arrest at 6 and 24 hours following the return of spontaneous circulation, and from sham control pigs. Sequencing results revealed changes in the proportions of different cell types, suggesting post-arrest disruption in the blood–brain barrier and infiltration of neutrophils. These results were validated through western blotting, quantitative reverse transcription-polymerase chain reaction, and immunofluorescence staining. We also identified and validated a unique subcluster of activated microglia with high expression of S100A8, which increased over time following cardiac arrest. This subcluster simultaneously exhibited significant M1/M2 polarization and expressed key functional genes related to chemokines and interleukins. Additionally, we revealed the post-cardiac arrest dysfunction of oligodendrocytes and the differentiation of oligodendrocyte precursor cells into oligodendrocytes. Cell communication analysis identified enhanced post–cardiac arrest communication between neutrophils and microglia that was mediated by neutrophil-derived resistin, driving pro-inflammatory microglial polarization. Our findings provide a comprehensive single-cell map of the post-cardiac arrest hippocampus, offering potential novel targets for neuroprotection and repair following cardiac arrest. Related Articles | Metrics

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Fibrotic scar formation after cerebral ischemic stroke: Targeting the Sonic hedgehog signaling pathway for scar reduction Jun Wen, Hao Tang, Mingfen Tian, Ling Wang, Qinghuan Yang, Yong Zhao, Xuemei Li, Yu Ren , Jiani Wang, Li Zhou, Yongjun Tan, Haiyun Wu, Xinrui Cai, Yilin Wang, Hui Cao, Jianfeng Xu, Qin Yang 2026, 21 (2):  756-768.  doi: 10.4103/NRR.NRR-D-24-00999 Abstract ( 34 )   PDF (7858KB) ( 5 )   Save Recent studies have shown that fibrotic scar formation following cerebral ischemic injury has varying effects depending on the microenvironment. However, little is known about how fibrosis is induced and regulated after cerebral ischemic injury. Sonic hedgehog signaling participates in fibrosis in the heart, liver, lung, and kidney. Whether Shh signaling modulates fibrotic scar formation after cerebral ischemic stroke and the underlying mechanisms are unclear. In this study, we found that Sonic Hedgehog expression was upregulated in patients with acute ischemic stroke and in a middle cerebral artery occlusion/reperfusion injury rat model. Both Sonic hedgehog and Mitofusin 2 showed increased expression in the middle cerebral artery occlusion rat model and in vitro fibrosis cell model induced by transforming growth factor-beta 1. Activation of the Sonic hedgehog signaling pathway enhanced the expression of phosphorylated Smad 3 and Mitofusin 2 proteins, promoted the formation of fibrotic scars, protected synapses or promoted synaptogenesis, alleviated neurological deficits following middle cerebral artery occlusion/reperfusion injury, reduced cell apoptosis, facilitated the transformation of meninges fibroblasts into myofibroblasts, and enhanced the proliferation and migration of meninges fibroblasts. The Smad3 phosphorylation inhibitor SIS3 reversed the effects induced by Sonic hedgehog signaling pathway activation. Bioinformatics analysis revealed significant correlations between Sonic hedgehog and Smad3, between Sonic hedgehog and Mitofusin 2, and between Smad3 and Mitofusin 2. These findings suggest that Sonic hedgehog signaling may influence Mitofusin 2 expression by regulating Smad3 phosphorylation, thereby modulating the formation of early fibrotic scars following cerebral ischemic stroke and affecting prognosis. The Sonic Hedgehog signaling pathway may serve as a new therapeutic target for stroke treatment. Related Articles | Metrics

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Sox2-overexpressing neural stem cells alleviate ventricular enlargement and neurological dysfunction in posthemorrhagic hydrocephalus Baocheng Gao, Haoxiang Wang, Shuang Hu, Kunhong Zhong, Xiaoyin Liu, Ziang Deng, Yuanyou Li, Aiping Tong, Liangxue Zhou 2026, 21 (2):  769-779.  doi: 10.4103/NRR.NRR-D-24-01491 Abstract ( 37 )   PDF (5231KB) ( 5 )   Save Neural stem cells (NSCs) have the potential for self-renewal and multidirectional differentiation, and their transplantation has achieved good efficacy in a variety of diseases. However, only 1%–10% of transplanted NSCs survive in the ischemic and hypoxic microenvironment of posthemorrhagic hydrocephalus. Sox2 is an important factor for NSCs to maintain proliferation. Therefore, Sox2-overexpressing NSCs (NSCSox2) may be more successful in improving neurological dysfunction after posthemorrhagic hydrocephalus. In this study, human NSCSox2 was transplanted into a posthemorrhagic hydrocephalus mouse model, and retinoic acid was administered to further promote NSC differentiation. The results showed that NSCSox2 attenuated the ventricular enlargement caused by posthemorrhagic hydrocephalus and improved neurological function. NSCSox2 also promoted nerve regeneration, inhibited neuroinflammation and promoted M2 polarization (antiinflammatory phenotype), thereby reducing cerebrospinal fluid secretion in choroid plexus. These findings suggest that NSCSox2 rescued ventricular enlargement and neurological dysfunction induced by posthemorrhagic hydrocephalus through neural regeneration and modulation of inflammation. Related Articles | Metrics

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A single-cell landscape of the regenerating spinal cord of zebrafish Lei Yao, Xinyi Cai, Saishuai Yang, Yixing Song, Lingyan Xing, Guicai Li, Zhiming Cui, Jiajia Chen 2026, 21 (2):  780-789.  doi: 10.4103/NRR.NRR-D-24-01163 Abstract ( 47 )   PDF (8990KB) ( 6 )   Save Unlike mammals, zebrafish possess a remarkable ability to regenerate their spinal cord after injury, making them an ideal vertebrate model for studying regeneration. While previous research has identified key cell types involved in this process, the underlying molecular and cellular mechanisms remain largely unexplored. In this study, we used single-cell RNA sequencing to profile distinct cell populations at different stages of spinal cord injury in zebrafish. Our analysis revealed that multiple subpopulations of neurons showed persistent activation of genes associated with axonal regeneration post injury, while molecular signals promoting growth cone collapse were inhibited. Radial glial cells exhibited significant proliferation and differentiation potential post injury, indicating their intrinsic roles in promoting neurogenesis and axonal regeneration, respectively. Additionally, we found that inflammatory factors rapidly decreased in the early stages following spinal cord injury, creating a microenvironment permissive for tissue repair and regeneration. Furthermore, oligodendrocytes lost maturity markers while exhibiting increased proliferation following injury. These findings demonstrated that the rapid and orderly regulation of inflammation, as well as the efficient proliferation and redifferentiation of new neurons and glial cells, enabled zebrafish to reconstruct the spinal cord. This research provides new insights into the cellular transitions and molecular programs that drive spinal cord regeneration, offering promising avenues for future research and therapeutic strategies. Related Articles | Metrics

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Pathological axonal enlargement in connection with amyloidosis, lysosome destabilization, and bleeding is a major defect in Alzheimer’s disease Hualin Fu, Jilong Li, Chunlei Zhang, Guo Gao, Qiqi Ge, Xinping Guan, Daxiang Cui 2026, 21 (2):  790-799.  doi: 10.4103/NRR.NRR-D-24-01440 Abstract ( 33 )   PDF (13838KB) ( 4 )   Save Alzheimer’s disease is a multi-amyloidosis disease characterized by amyloid-β deposits in brain blood vessels, microaneurysms, and senile plaques. How amyloid-β deposition affects axon pathology has not been examined extensively. We used immunohistochemistry and immunofluorescence staining to analyze the forebrain tissue slices of Alzheimer’s disease patients. Widespread axonal amyloidosis with distinctive axonal enlargement was observed in patients with Alzheimer’s disease. On average, amyloid-β-positive axon diameters in Alzheimer’s disease brains were 1.72 times those of control brain axons. Furthermore, axonal amyloidosis was associated with microtubule-associated protein 2 reduction, tau phosphorylation, lysosome destabilization, and several blood-related markers, such as apolipoprotein E, alpha-hemoglobin, glycosylated hemoglobin type A1C, and hemin. Lysosome destabilization in Alzheimer’s disease was also clearly identified in the neuronal soma, where it was associated with the co-expression of amyloid-β, Cathepsin D, alpha-hemoglobin, actin alpha 2, and collagen type IV. This suggests that exogenous hemorrhagic protein intake influences neural lysosome stability. Additionally, the data showed that amyloid-β-containing lysosomes were 2.23 times larger than control lysosomes. Furthermore, under rare conditions, axonal breakages were observed, which likely resulted in Wallerian degeneration. In summary, axonal enlargement associated with amyloidosis, micro-bleeding, and lysosome destabilization is a major defect in patients with Alzheimer’s disease. This finding suggests that, in addition to the well-documented neural soma and synaptic damage, axonal damage is a key component of neuronal defects in Alzheimer’s disease. Related Articles | Metrics

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Topical administration of GLP-1 eyedrops improves retinal ganglion cell function by facilitating presynaptic GABA release in early experimental diabetes Yu-Qi Shao, Yong-Chen Wang, Lu Wang, Hang-Ze Ruan, Yun-Feng Liu, Ti-Hui Zhang, Shi-Jun Weng, Xiong-Li Yang, Yong-Mei Zhong 2026, 21 (2):  800-810.  doi: 10.4103/NRR.NRR-D-24-00001 Abstract ( 31 )   PDF (5067KB) ( 24 )   Save Diabetic retinopathy is a prominent cause of blindness in adults, with early retinal ganglion cell loss contributing to visual dysfunction or blindness. In the brain, defects in γ-aminobutyric acid synaptic transmission are associated with pathophysiological and neurodegenerative disorders, whereas glucagon-like peptide-1 has demonstrated neuroprotective effects. However, it is not yet clear whether diabetes causes alterations in inhibitory input to retinal ganglion cells and whether and how glucagon-like peptide-1 protects against neurodegeneration in the diabetic retina through regulating inhibitory synaptic transmission to retinal ganglion cells. In the present study, we used the patch-clamp technique to record γ-aminobutyric acid subtype A receptor–mediated miniature inhibitory postsynaptic currents in retinal ganglion cells from streptozotocin-induced diabetes model rats. We found that early diabetes (4 weeks of hyperglycemia) decreased the frequency of GABAergic miniature inhibitory postsynaptic currents in retinal ganglion cells without altering their amplitude, suggesting a reduction in the spontaneous release of γ-aminobutyric acid to retinal ganglion cells. Topical administration of glucagon-like peptide-1 eyedrops over a period of 2 weeks effectively countered the hyperglycemia-induced downregulation of GABAergic mIPSC frequency, subsequently enhancing the survival of retinal ganglion cells. Concurrently, the protective effects of glucagon-like peptide-1 on retinal ganglion cells in diabetic rats were eliminated by topical administration of exendin-9-39, a specific glucagon-like peptide-1 receptor antagonist, or SR95531, a specific antagonist of the γ-aminobutyric acid subtype A receptor. Furthermore, extracellular perfusion of glucagonlike peptide-1 was found to elevate the frequencies of GABAergic miniature inhibitory postsynaptic currents in both ON- and OFF-type retinal ganglion cells. This elevation was shown to be mediated by activation of the phosphatidylinositol-phospholipase C/inositol 1,4,5-trisphosphate receptor/Ca2+/protein kinase C signaling pathway downstream of glucagon-like peptide-1 receptor activation. Moreover, multielectrode array recordings revealed that glucagon-like peptide-1 functionally augmented the photoresponses of ON-type retinal ganglion cells. Optomotor response tests demonstrated that diabetic rats exhibited reductions in visual acuity and contrast sensitivity that were significantly ameliorated by topical administration of glucagon-like peptide-1. These results suggest that glucagon-like peptide-1 facilitates the release of γ-aminobutyric acid onto retinal ganglion cells through the activation of glucagon-like peptide-1 receptor, leading to the de-excitation of retinal ganglion cell circuits and the inhibition of excitotoxic processes associated with diabetic retinopathy. Collectively, our findings indicate that the γ-aminobutyric acid system has potential as a therapeutic target for mitigating early-stage diabetic retinopathy. Furthermore, the topical administration of glucagon-like peptide-1 eyedrops represents a non-invasive and effective treatment approach for managing early-stage diabetic retinopathy.  Related Articles | Metrics

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Zebrafish optic nerve regeneration involves resident and retinal oligodendrocytes Cristina Pérez-Montes, Rosalía Hernández-García, Jhoana Paola Jiménez-Cubides, Laura DeOliveira-Mello, Almudena Velasco, Rosario Arévalo, Marina García-Macia, Adrián Santos-Ledo 2026, 21 (2):  811-820.  doi: 10.4103/NRR.NRR-D-24-00621 Abstract ( 42 )   PDF (79851KB) ( 4 )   Save The visual system of teleost fish grows continuously, which is a useful model for studying regeneration of the central nervous system. Glial cells are key for this process, but their contribution is still not well defined. We followed oligodendrocytes in the visual system of adult zebrafish during regeneration of the optic nerve at 6, 24, and 72 hours post-lesion and at 7 and 14 days post-lesion via the sox10:tagRFP transgenic line and confocal microscopy. To understand the changes that these oligodendrocytes undergo during regeneration, we used Sox2 immunohistochemistry, a stem cell marker involved in oligodendrocyte differentiation. We also used the Click-iT™ Plus TUNEL assay to study cell death and a BrdU assay to determine cell proliferation. Before optic nerve crush, sox10:tagRFP oligodendrocytes are located in the retina, in the optic nerve head, and through all the entire optic nerve. Sox2-positive cells are present in the peripheral germinal zone, the mature retina, and the optic nerve. After optic nerve crush, sox10:tagRFP cells disappeared from the optic nerve crush zone, suggesting that they died, although they were not TUNEL positive. Concomitantly, the number of Sox2-positive cells increased around the crushed area, the optic nerve head, and the retina. Then, between 24 hours post-lesion and 14 days post-lesion, double sox10:tagRFP/Sox2-positive cells were detected in the retina, optic nerve head, and whole optic nerve, together with a proliferation response at 72 hours post-lesion. Our results confirm that a degenerating process may occur prior to regeneration. First, sox10:tagRFP oligodendrocytes that surround the degenerated axons stop wrapping them, change their “myelinating oligodendrocyte” morphology to a “nonmyelinating oligodendrocyte” morphology, and die. Then, residual oligodendrocyte progenitor cells in the optic nerve and retina proliferate and differentiate for the purpose of remyelination. As new axons arise from the surviving retinal ganglion cells, new sox10:tagRFP oligodendrocytes arise from residual oligodendrocyte progenitor cells to guide, nourish and myelinate them. Thus, oligodendrocytes play an active role in zebrafish axon regeneration and remyelination. Related Articles | Metrics

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Mesenchymal stem cell–derived small extracellular vesicles enhance the therapeutic effect of retinal progenitor cells in retinal degenerative disease rats Chunge Ren, Min Chen, Bangqi Ren, Yuxiao Zeng, Qiang Tan, Qiyou Li, Xue Zhang, Yajie Fang, Yixiao Zhou, Weitao Zhang, Fang Chen, Baishijiao Bian, Yong Liu 2026, 21 (2):  821-832.  doi: 10.4103/NRR.NRR-D-23-02108 Abstract ( 34 )   PDF (8644KB) ( 8 )   Save Our previous study demonstrated that combined transplantation of bone marrow mesenchymal stem cells and retinal progenitor cells in rats has therapeutic effects on retinal degeneration that are superior to transplantation of retinal progenitor cells alone. Bone marrow mesenchymal stem cells regulate and interact with various cells in the retinal microenvironment by secreting neurotrophic factors and extracellular vesicles. Small extracellular vesicles derived from bone marrow mesenchymal stem cells, which offer low immunogenicity, minimal tumorigenic risk, and ease of transportation, have been utilized in the treatment of various neurological diseases. These vesicles exhibit various activities, including anti-inflammatory actions, promotion of tissue repair, and immune regulation. Therefore, novel strategies using human retinal progenitor cells combined with bone marrow mesenchymal stem cell–derived small extracellular vesicles may represent an innovation in stem cell therapy for retinal degeneration. In this study, we developed such an approach utilizing retinal progenitor cells combined with bone marrow mesenchymal stem cell–derived small extracellular vesicles to treat retinal degeneration in Royal College of Surgeons rats, a genetic model of retinal degeneration. Our findings revealed that the combination of bone marrow mesenchymal stem cell-derived small extracellular vesicles and retinal progenitor cells significantly improved visual function in these rats. The addition of bone marrow mesenchymal stem cell–derived small extracellular vesicles as adjuvants to stem cell transplantation with retinal progenitor cells enhanced the survival, migration, and differentiation of the exogenous retinal progenitor cells. Concurrently, these small extracellular vesicles inhibited the activation of regional microglia, promoted the migration of transplanted retinal progenitor cells to the inner nuclear layer of the retina, and facilitated their differentiation into photoreceptors and bipolar cells. These findings suggest that bone marrow mesenchymal stem cell–derived small extracellular vesicles potentiate the therapeutic efficacy of retinal progenitor cells in retinal degeneration by promoting their survival and differentiation. Related Articles | Metrics