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15 July 2026, Volume 21 Issue 7 Previous Issue   

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Evolution of neutrophil extracellular traps in the pathology of stroke Wenjing Ning, Qian Wang, Yuzhen Xu 2026, 21 (7):  2501-2525.  doi: 10.4103/NRR.NRR-D-25-00364 Abstract ( 105 )   PDF (11012KB) ( 45 )   Save Stroke is a major cause of death and disability worldwide, and its pathogenesis is complex, involving multiple pathological processes, such as thrombosis, ischemia-reperfusion injury, inflammatory response, and blood–brain barrier disruption. In recent years, neutrophil extracellular traps have been found to be involved in the body’s anti-infection defense and to play an important role in stroke. Studies have shown that neutrophil extracellular traps promote thrombus expansion and neuroinflammation in ischemic stroke, and they may be involved in disease progression and recovery in hemorrhagic stroke by modulating local inflammation and influencing hematoma clearance. This review systematically summarizes the evolution and mechanism of action of neutrophil extracellular traps in stroke pathology. Reactive oxygen species drive the formation of neutrophil extracellular traps 6–24 hours after cerebral infarction. At 24–48 hours, they exacerbate vascular injury and thrombosis, at 48–72 hours, they aggravate neurological injury, and after 72 hours, neutrophil extracellular traps are involved in the disruption of the blood–brain barrier and the maintenance of the inflammatory response. During stroke development, neutrophil extracellular traps are involved in multiple pathological mechanisms after cerebral infarction. They induce vascular endothelial damage, exacerbating vascular leakage and edema, injuring neurons, inducing apoptosis, promoting thrombosis, participating in reperfusion injury, and damaging the blood–brain barrier. In hemorrhagic stroke, neutrophil extracellular traps are closely associated with hematoma clearance, early brain injury, and delayed cerebral ischemia, and can be used as a biomarker to assess disease progression and efficacy. In the acute phase of stroke, neutrophil extracellular traps mainly promote injury, and in the chronic phase, they mainly promote repair. Neutrophil extracellular traps, as an important biomarker of stroke, are closely correlated with stroke severity. Additionally, neutrophil extracellular traps play an important role in atherosclerosis and intracranial venous thrombosis. Current research has confirmed that deoxyribonuclease is a key drug for degrading neutrophil extracellular traps and has shown significant therapeutic potential. Peptidyl arginine deiminase 4 inhibitors and high mobility group box 1 antagonists effectively inhibit the formation of neutrophil extracellular traps through their own unique mechanisms. Multi-targeted intervention strategies for neutrophil extracellular traps have shown broad clinical application prospects. Neutrophil extracellular traps exhibit synergistic effects with anticoagulants and thrombolytic drugs, and interventions targeting neutrophil extracellular traps can influence the efficacy of anticoagulation and thrombolytic therapy. These findings provide a theoretical basis for developing new anticoagulation and thrombolysis strategies for stroke and improving clinical outcomes for patients. Related Articles | Metrics

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Biomarker advancements in cerebral small vessel disease: An overview Wenqian Luo, Chenhui Cao, Wenli Li, Ting Wei, Zeyu Zhao, Guanqing Wang, Xiaoli Li, Yanbin Li , Bin Liu 2026, 21 (7):  2526-2540.  doi: 10.4103/NRR.NRR-D-24-01329 Abstract ( 63 )   PDF (2193KB) ( 117 )   Save Cerebral small vessel disease is a condition caused by chronic cerebral hypoperfusion due to microvascular damage and is a major contributor to stroke and dementia. Traditionally, its diagnosis has relied primarily on neuroimaging findings. However, recent advances in the understanding of cerebral small vessel disease pathophysiology have opened new avenues for early detection and targeted therapeutic interventions. Notably, the identification and investigation of cerebral small vessel disease–related biomarkers have emerged as a promising strategy for early diagnosis. This review provides an overview of recent research on cerebral small vessel disease biomarkers, including plasma biomarkers, cerebrospinal fluid biomarkers, and genetic markers. Finally, we discuss future directions and trends in the clinical validation of these biomarkers. Related Articles | Metrics

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Magnesium and nerve injury: Mechanisms and applications Hongye Yan , Su Pan , Longchuan Zhu , Weijian Kong , Zhiping Qi 2026, 21 (7):  2541-2554.  doi: 10.4103/NRR.NRR-D-25-00263 Abstract ( 68 )   PDF (3553KB) ( 142 )   Save Magnesium is a vital mineral that plays an important role in recovery from nerve injury recovery by inhibiting excitotoxicity, suppressing inflammatory effects, reducing oxidative stress, and protecting mitochondria. The role of magnesium ions in the field of nerve injury repair has garnered substantial attention. This paper aims to review the mechanisms of action and potential applications of magnesium in nerve injury repair. Magnesium ions, as key neuroregulatory factors, substantially alleviate secondary damage after nerve injury by inhibiting N-methyl-D-aspartate receptors, regulating calcium ion balance, providing anti-inflammatory and antioxidant effects, and protecting mitochondrial function. Magnesium ions have been shown to reduce neuronal death caused by excitotoxicity, inhibit the release of inflammatory factors, and improve mitochondrial function. Additionally, magnesium materials, such as metallic magnesium, magnesium alloys, surface-modified magnesium materials, and magnesium-based metallic glass, exhibit unique advantages in nerve repair. For example, magnesium materials can control the release of magnesium ions, thereby promoting axonal regeneration and providing mechanism support. However, the rapid corrosion of magnesium materials and the limited amount of research on these materials hinder their widespread application. Existing small-sample clinical studies have indicated that magnesium formulations show some efficacy in conditions such as migraines, Alzheimer’s disease, and traumatic brain injury, offering a new perspective for the application of magnesium in nerve injury rehabilitation. Magnesium ions and their derived materials collectively hold great promise for applications in nerve injury repair. Future efforts should focus on in-depth research on the mechanisms of action of magnesium ions and the development of magnesium-based biomaterials with enhanced performance. Additionally, large-scale clinical trials should be conducted to validate their safety and efficacy. Related Articles | Metrics

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Intriguing role of the Golgi apparatus in astrocyte function: Implications for disorders Martina Polenghi, Elena Restelli, Elena Taverna , Laura Tapella 2026, 21 (7):  2555-2562.  doi: 10.4103/NRR.NRR-D-25-00342 Abstract ( 49 )   PDF (1867KB) ( 14 )   Save Cell function has a tight relationship with cell architecture. Distribution of proteins to the correct compartment is one of the functions of the traffic pathway through the Golgi apparatus. The others are to ensure proper protein folding, the addition of post-translational modifications, and delivering to intracellular and extracellular destinations. Astrocytes are fundamental homeostatic cells, controlling multiple aspects of the central nervous system physiology, such as ion balance, nutrients, blood flow, neurotransmitters, and responses to insults. Astrocytes are polarized cells, and, such as neurons, extensively use the secretory pathway for secreting factors and exposing functional receptors, channels, and transporters on the plasma membrane. In this review, we will underline the importance of studying the Golgi apparatus and the secretory pathway in astrocytes, based on the possible tight connection between the Golgi apparatus and astrocytes’ homeostatic function. Given the topic of this review, we will provide examples mostly about the Golgi apparatus structure, function, localization, and its involvement in astrocytes’ homeostatic response, with an insight into congenital glycosylation disorders, as an example of a potential future field in the study of astrocyte homeostatic failure and Golgi apparatus alteration. Related Articles | Metrics

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Six promising drug repurposing candidates for Alzheimer’s disease and their sex-specific mechanisms and efficacy Maria E. Figueiredo-Pereira, Peter A. Serrano, Patricia Rockwell 2026, 21 (7):  2563-2571.  doi: 10.4103/NRR.NRR-D-25-00256 Abstract ( 42 )   PDF (2101KB) ( 24 )   Save Alzheimer’s disease is a neurodegenerative disorder that leads to progressive memory loss, cognitive decline, and behavioral changes. Despite ongoing research, its exact causes and effective treatments remain elusive. Traditional approaches have focused on symptom management, but breakthroughs in bioinformatics and high-throughput drug screening are offering new pathways to potential therapies. This review highlights our recent efforts to identify novel drug candidates for Alzheimer’s disease by leveraging computational methods and large-scale biological datasets. Our work introduces two key innovations in Alzheimer’s disease research: addressing sex-specific differences and leveraging drug repurposing for accelerated treatment discovery. By combining sex-stratified preclinical data with machine learning and in vivo validation, we improve translational relevance and support precision medicine. Using the TgF344-AD rat model, which mimics human Alzheimer’s disease spatial memory deficits and pathology, we explored the efficacy of various US Food and Drug Administration– approved and investigational drugs. These included ibudilast, timapiprant, RG2833, diazoxide/ dibenzoylmethane (combined), and BT-11, which targeted key Alzheimer’s disease–related molecular pathways such as amyloid-beta plaques, Tau tangles, and neuroinflammation. These drugs, at various stages of development, offer hope for not only managing symptoms but also addressing the underlying mechanisms of Alzheimer’s disease. This review underscores the need for a multifaceted approach to Alzheimer’s disease treatment, combining symptom relief with disease modification. Related Articles | Metrics

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Palmitic acid–induced autolysosomal dysfunction and lipotoxicity in neuroinflammation and neurodegeneration Eka Norfaishanty Saipuljumri, Jialiu Zeng, Chih Hung Lo 2026, 21 (7):  2572-2579.  doi: 10.4103/NRR.NRR-D-25-00432 Abstract ( 48 )   PDF (2553KB) ( 19 )   Save Neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases are increasingly associated with metabolic dysfunction, including obesity, type 2 diabetes, and metabolic dysfunction–associated steatotic liver disease. Central to this connection is the dysregulation of lipid metabolism, which extends beyond peripheral tissues to the brain, defective autolysosomal function, oxidative stress, inflammation, and insulin resistance. Lipids, which constitute over half of dry weight of the brain, play critical roles in energy provision, structural integrity, and synaptic function. Dysregulation of lipid metabolism contributes to neuroinflammation, impaired neuronal function, and disrupted blood–brain barrier integrity. Palmitic acid, a saturated fatty acid abundant in high-fat diets, serves as a key model for studying lipid-induced toxicity (lipotoxicity) in the brain. Palmitic acid disrupts autophagy and lysosomal function, mitochondrial function, triggering oxidative stress, contributing to neuroinflammation and neurodegeneration. These effects are particularly pronounced in neurons, which are highly susceptible to lipid-induced toxicity due to their high metabolic demands. Glial cells, including astrocytes, microglia, and oligodendrocytes, also exhibit distinct vulnerabilities and adaptive responses to lipid metabolism dysregulation, further contributing to neuroinflammation and demyelination. Therapeutic strategies, such as supplementation with polyunsaturated fatty acids, AMP-activated protein kinase activation, and lysosome-targeted interventions, show promise in mitigating palmitic acid–induced lipotoxicity and restoring cellular homeostasis. This review comprehensively examines palmitic acid–induced lipotoxicity and its impact on autolysosomal dysfunction across various central nervous system cell types, including neurons, astrocytes, microglia, and oligodendrocytes. Additionally, it highlights therapeutic approaches to restore autolysosomal function under lipotoxic conditions. Advances in multi-omics technologies and a deeper understanding of intercellular crosstalk offer new avenues for developing targeted therapies to restore autolysosomal function, and attenuate neuroinflammation and neurodegeneration. Related Articles | Metrics

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Advances and applications of brain organoids in central nervous system disorders: Bridging the gap from laboratory to clinic Changle Fang, Qiulin Wang, Qiuxia Xiao, Xiaoxing Cai, Ruolan Du, Lulu Xue, Xiaohe Tian, Liulin Xiong 2026, 21 (7):  2580-2600.  doi: 10.4103/NRR.NRR-D-24-01490 Abstract ( 66 )   PDF (5449KB) ( 68 )   Save Investigating the mechanisms underlying central nervous system disorders is a major scientific issue in the 21st century. However, the inaccessibility and complexity of the human brain have always represented a challenge in understanding the pathophysiology of the central nervous system. Brain organoids are self-assembled three-dimensional aggregates derived from pluripotent stem cells with cell types and structures similar to the embryonic human brain, giving them potential for investigating the atypical cellular, molecular, and genetic characteristics characteristic of central nervous system disorders. Brain organoids also provide a platform for drug screening and serve as a potential source for transplantation therapy for brain injuries. However, the broad application of brain organoids is hampered by several limitations, such as the lack of high-fidelity cell types, insufficient maturation, and considerable heterogeneity, undermining their reliability in specific applications. This review summarizes brain organoid evolution, discusses recent technological and methodological innovations, and reviews their applications in drug screening, transplantation therapy, and disease modeling, as well as clinical research progress. Additionally, we emphasize the limitations of current brain organoid research and explore the potential for advancing the technology to enhance its applicability. Related Articles | Metrics

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Emerging role of copper in the pathophysiology of spinal cord injury Wenjing Ni, Peiling Qiu, Yang Huang, Sheng Wang, Xiaolei Zhang, Yifei Zhou, Di Zhang 2026, 21 (7):  2601-2624.  doi: 10.4103/NRR.NRR-D-24-01449 Abstract ( 44 )   PDF (9204KB) ( 20 )   Save Copper is a trace element that plays an important role in neuronal development, maturation, and function. It also acts as a cofactor for various copper-binding proteins or serves as an active component of their structure. Acquired copper deficiency has been associated with numerous neurological diseases. Recent research has demonstrated that serum copper concentrations are elevated following spinal cord injury, similar to the elevated copper levels observed after ischemic insult in a rat model of myocardial infarction. This suggests that spinal cord damage may impair the effective utilization of copper due to local ischemia following spinal cord injury. Studies have shown that copper supplementation may form part of a therapeutic strategy for patients with spinal cord injury. It has been reported to promote T-cell differentiation and proliferation, reduce malondialdehyde levels, decrease myeloperoxidase activity and apoptotic cell numbers, and enhance superoxide dismutase activity and glutathione levels. Additionally, copper supplementation may stimulate the transcriptional activity of hypoxia-inducible factor and restore angiogenic capacity, thereby increasing capillary density. Furthermore, researchers have found that dihydrolipoamide dehydrogenase, an enzyme involved in inducing cuproptosis, can influence the immune microenvironment of spinal cord injury by promoting copper toxicity. This leads to increased peripheral M2 macrophage polarization and systemic immunosuppression. This led us to hypothesize that copper may influence three major pathological pathways after spinal cord injury, inflammation, oxidative stress, and cell death, which are critical targets for therapeutic intervention. On the one hand, copper deficiency can cause spinal cord tissue damage; on the other hand, elevated serum copper may induce copper toxicity, contributing to cell death. Therefore, in this review, we investigate the possible link between spinal cord injury and copper in the perspective of inflammation, oxidative stress, and cell death. Additionally, we review published studies on copper metabolism and explore potential therapeutic strategies by considering various sources and mechanisms of copper delivery. Related Articles | Metrics

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MicroRNAs in the pathogenesis of neurodegenerative disorders: Potential as therapeutic targets Aditi Singh , Manivannan Subramanian , Amit Singh 2026, 21 (7):  2625-2633.  doi: 10.4103/NRR.NRR-D-25-00402 Abstract ( 27 )   PDF (1516KB) ( 19 )   Save Neurodegenerative diseases (neurodegenerative disorders) are marked by the progressive degeneration of the structure and function of the central nervous system. They may result in the deterioration of cognitive, motor, and functional abilities. Diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis represent some of the most prominent examples of neurodegenerative disorders. Despite scientific advancement in understanding disease pathology and prognosis, the therapeutic strategies available for management remain limited. In recent years, microRNAs, small non-coding RNA molecules, have emerged as key players in the pathogenesis of neurodegenerative disorders. Therefore, understanding how these microRNAs affect disease pathology and pathway signaling is essential, and may open microRNAs as new avenues for potential therapeutic intervention. This review explores the role of microRNAs in various neurodegenerative diseases, discuss how microRNAs affect signaling pathways, and examine the potential of microRNAs as therapeutic targets. Related Articles | Metrics

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Deep brain stimulation of the nucleus basalis of Meynert in neurodegenerative diseases with cognitive impairment: An update on evidence and mechanisms Xuyang Liu , Kai Shu , Liwu Jiao , Yumei Geng , Mengying Wang , Huicong Kang 2026, 21 (7):  2634-2648.  doi: 10.4103/NRR.NRR-D-24-00838 Abstract ( 43 )   PDF (10549KB) ( 5 )   Save Current pharmacotherapy for neurodegenerative diseases is limited to providing symptomatic relief, instead of slowing or reversing disease progression. As a form of neuromodulation surgery, deep brain stimulation delivers electrical pulses through implanted electrodes in targeted brain regions and has been used to alleviate symptoms in neurodegenerative diseases. Depending on the precise targeting of neural modulation, deep brain stimulation is being explored for its potential to manage symptoms and improve overall quality of life in neurodegenerative diseases associated with cognitive impairment, such as Alzheimer’s disease and dementia in Parkinson’s disease. The nucleus basalis of Meynert, a critical component of the cerebral cholinergic system and the Papez circuit, is considered as a promising target for treating cognitive dysfunction in neurodegenerative diseases due to its essential role in regulating cognition, memory, and attention. However, the comprehensive mechanisms by which deep brain stimulation of nucleus basalis of Meynert affects neurodegenerative diseases with cognitive impairment remain largely uncharacterized. Nonetheless, various hypotheses and evidence from animal and clinical studies suggest mechanisms such as the modeulation of the cholinergic system, increased glucose metabolism and regional cerebral blood flow, neuroprotective effects, and the modulation of neural networks. In this review, we update the advances in research regarding the therapeutic effects and potential mechanisms of deep brain stimulation of nucleus basalis of Meynert on cognitive impairment in neurodegenerative diseases. Additionally, we examine the anatomy, connectivity, and physiological functions of the nucleus basalis of Meynert. Deep brain stimulation of nucleus basalis of Meynert may improve cognitive impairment in neurodegenerative diseases through multiple mechanisms; however, further larger-scale, multi-center clinical trials conducted at earlier disease stages are necessary to fully confirm its efficacy and safety. Related Articles | Metrics

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Decellularized matrix grafts and peripheral nerve regeneration Qin Zhang, Xingyu Liu, Ye Zhu, Tianmei Qian, Shanshan Wang, Meiyuan Li 2026, 21 (7):  2649-2669.  doi: 10.4103/NRR.NRR-D-25-00526 Abstract ( 51 )   PDF (28856KB) ( 20 )   Save Traditional nerve repair methods, such as autologous nerve grafting and allogeneic nerve grafting, face issues such as donor shortage, functional loss, and immune rejection. Decellularized extracellular matrix-based grafts have emerged as highly promising alternatives, capable of uniquely recreating the natural neural microenvironment, promoting host cell remodeling, and ultimately enhancing functional neural regeneration. This review comprehensively analyzes the key mechanisms of peripheral nerve injury and regeneration, focusing on contemporary therapeutic strategies for key aspects such as axonal apoptosis inhibition, enhanced intrinsic regenerative capacity, construction of regenerative microenvironment, and prevention of target organ atrophy. Findings from this review has shown that decellularized extracellular matrix grafts can promote the migration, proliferation, and differentiation of nerve cells by providing physical support, chemical signals, and mechanical stability. Decellularized extracellular matrix grafts are mainly used as nerve conduits, scaffolds, hydrogels, and 3D printing inks. Decellularized extracellular matrix grafts have demonstrated significant advantages in promoting nerve regeneration by regulating the proliferation and differentiation of Schwann cells, improving the neural microenvironment, reducing inflammatory responses, and promoting angiogenesis. Additionally, decellularized extracellular matrix grafts can serve as drug carriers, enabling the controlled release of growth factors, which further enhances nerve regeneration. However, these grafts also have some limitations, including the presence of immunogenic residues, inadequate mechanical properties, inter-batch variability, and uncontrollable degradation rates. Future research should focus on optimizing the decellularization process, enhancing the mechanical properties of decellularized extracellular matrix grafts, reducing immunogenicity, improving biocompatibility and safety, and developing new composite materials. Furthermore, exploring their application potential in complex nerve injuries, such as diabetic neuropathy, is crucial to meet the needs of peripheral nerve regeneration and repair. Related Articles | Metrics

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Phosphatase and tensin homolog: A potential target for therapeutic intervention in optic nerve regeneration Bin Tong, Yanzhuo Song, Zhengyang Li, Muhan Cai, Haodong Qi, Kangtai Su, Hong A. Xu 2026, 21 (7):  2670-2683.  doi: 10.4103/NRR.NRR-D-24-01599 Abstract ( 43 )   PDF (1703KB) ( 70 )   Save Recent studies have found that the suppression of phosphatase and tensin homolog is one of the most effective single-gene approaches for promoting optic nerve regeneration. This effect is primarily mediated through the activation of the protein kinase B/phosphoinositide 3-kinase/mammalian target of rapamycin signaling pathway. The purpose of this article is to elucidate how the downregulation of phosphatase and tensin homolog is involved in each key phase of optic nerve regeneration and to summarize the potential targets for therapeutic interventions in this process. Optic nerve regeneration progresses through five phases: stress response, growth navigation, nerve regeneration, synaptic reconstruction, and remyelination. During the stress response phase, the suppression of phosphatase and tensin homolog enhances the survival of retinal ganglion cells and promotes the proliferation of microglia. In the nerve regeneration phase, reduced levels of phosphatase and tensin homolog facilitate mitochondrial transport, while inhibition of the phosphatase and tensin homolog-L isoform specifically promotes mitophagy. During the synaptic reconstruction phase, the deletion of phosphatase and tensin homolog modulates the synthesis of axon extension-related proteins and stabilizes microglial microtubules, thereby accelerating the clearance of damaged synapses and the formation of new ones. During the remyelination phase, the knockout of phosphatase and tensin homolog promotes the proliferation of oligodendrocyte progenitor cells and the differentiation of oligodendrocytes, relieving myelination obstruction. This paper also discusses current strategies and translational challenges for neuron-specific inhibition of phosphatase and tensin homolog, including off-target effects, delivery precision, and long-term safety. By integrating molecular insights with emerging bioengineering approaches, this paper provides a framework for developing targeted therapies for optic nerve regeneration and broader applications in the field of central nervous system regeneration. Related Articles | Metrics

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Interplay between brain-specific microRNAs and Alzheimer’s disease Nathan Tinu, Bhupender Sharma, Daniela Rodarte, Rajkumar Lakshmanaswamy, Subodh Kumar 2026, 21 (7):  2684-2698.  doi: 10.4103/NRR.NRR-D-25-00190 Abstract ( 44 )   PDF (1272KB) ( 17 )   Save Alzheimer’s disease is a progressive neurodegenerative disease characterized by memory decline and the accumulation of abnormal protein aggregates in the brain. While the precise cause of Alzheimer’s disease remains under investigation, recent research suggests that dysregulation of brainspecific microRNAs (miRs) plays a significant role in Alzheimer’s disease pathogenesis. Brain-specific miRs are predominantly expressed within the central nervous system and are crucial for neuronal development, and function, potentially in brain disorders. This review identifies some key brainspecific miRs in Alzheimer’s disease, including miR-9, miR-26b, miR-34a, miR-107, miR-124, miR125b, miR-128, miR-132, miR-146a, miR-155, miR-219, miR-501-3p, and miR-502-3p. The review also shed light on the brain-specific location of these miRs, their dysregulation in Alzheimer’s disease, and how they are involved in disease progression. Apparently, these brain-specific miRs modulate specific genes and are therefore crucial for various cellular processes, including autophagy, cell cycle, tau phosphorylation, amyloid-beta production, and neuroinflammation. Moreover, these miRs are potent disease-modifying factors and their expression levels could serve as potential biomarkers for diagnosing or monitoring Alzheimer’s disease progression. Related Articles | Metrics

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Brain organoids and genome editing: A new era in understanding human brain development and disorders Min Zhou, Yuanqing Cao, Ke Yue, Wenyu Wu, Yutong Xie, Daiyu Hu, Jingjing Zhao, Fang Xu, Jianrong Guo, Zhenzhou Li, Huan Wang, Zhengliang Gao 2026, 21 (7):  2699-2715.  doi: 10.4103/NRR.NRR-D-24-01546 Abstract ( 41 )   PDF (2291KB) ( 99 )   Save Brain organoids are artificial neural tissues derived in vitro, containing a variety of cell types, as well as structural and/or functional brain regions. They can partially mimic brain physiological activities and diseased processes. Owing to their operability and sample accessibility, brain organoids serve as a bridge between in vitro monolayer cell culture models and in vivo animal models. An increasing number of induction protocols for brain organoids have been developed over the preceding decade. A key future research direction will focus on ensuring the complexity and quality of brain organoids. The integration of powerful technologies, such as the CRISPR/Cas9 genome editing and lineage tracing systems, shall precipitate practical and broad applications of brain organoids. In this review, we discuss the generation and application of brain organoids, as well as their integration with genome editing technologies, in the study of neural development, disease modeling, and mechanistic investigations. The innovative combination of these two technologies may offer a fresh perspective for exploring the fundamental aspects of the human nervous system and related diseases. Related Articles | Metrics

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MicroRNA and Alzheimer’s disease: Diagnostic biomarkers and potential therapeutic targets Yiwen Huang, Yimin Chen, Zhengyang He, Wenfeng Lu, Hejin Lai, Yu Wang, Jie Wang 2026, 21 (7):  2716-2741.  doi: 10.4103/NRR.NRR-D-25-00002 Abstract ( 38 )   PDF (7939KB) ( 11 )   Save MicroRNAs (miRNAs), small non-coding RNAs ranging from 19 to 25 nucleotides in length, are key regulators of gene expression that function primarily by inhibiting the translation of target mRNAs. Recent studies have suggested that miRNAs play important roles in regulating key aspects in the pathology of Alzheimer’s disease, including the modulation and accumulation of amyloid-beta and tau proteins. Moreover, miRNAs have been implicated in the regulation of neuroinflammation through various inflammatory pathways, notably the nuclear factor kappa B signaling cascade. Additional emerging evidence has shown that miRNAs regulate synaptic growth and maturation, and they perform promising roles in regulating neuronal death and development. miRNAs also offer a novel avenue for direct reprogramming of neurons, representing a promising strategy for Alzheimer’s disease treatment. The regulation of miRNA biogenesis and the post-transcriptional modifications of miRNAs are critical factors in Alzheimer’s disease pathology, influencing miRNA activity and disease progression. In this review, we comprehensively explore the role of different miRNAs in regulating various pathological processes associated with Alzheimer’s disease, focusing primarily on four representative miRNAs: miR-9, miR-29, miR-126, and miR-146a for further exploration. We also discuss the influence of miRNA biogenesis on Alzheimer’s disease, emphasizing how dysregulation of miRNA processing may contribute to the disease. Additionally, we highlight the potential of miRNAs as both diagnostic biomarkers and therapeutic targets in Alzheimer’s disease, along with promising vector delivery strategies aimed at improving clinical outcomes. Finally, we discuss the challenges and limitations associated with the use of miRNAs in the diagnosis and treatment of Alzheimer’s disease. By reviewing the current clinical applications of miRNAs as biomarkers and therapeutic agents, we aim to provide insights that will inform future research and development in this promising field. Related Articles | Metrics

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Application strategies of autologous and decellularized nerve grafts: Structural and functional recovery Xiaoqi Yang, Nianci Huo, Hui Zhou, Senrui Li, Mengyuan Fang, Nan Zhou 2026, 21 (7):  2742-2768.  doi: 10.4103/NRR.NRR-D-25-00607 Abstract ( 53 )   PDF (5891KB) ( 51 )   Save Autologous nerve transplantation is currently recognized as the gold standard for treating severe peripheral nerve injuries in clinical practice. However, challenges such as a limited supply of donors, complications in the donor area, and the formation of neuromas necessitate the optimization of existing transplantation strategies. Additionally, the development of new and promising repair methods is a critical issue in the field of peripheral nerve research. The purpose of this article is to compare the advantages and disadvantages of autologous, allogeneic, decellularized nerve grafts, and cell-composite graft, as well as to summarize the differences in their prognostic factors and associated adverse events. The length, diameter, polarity, and sensory or motor origin of autografts all influence axonal regeneration. While pre-denaturation treatment can accelerate early regeneration, long-term functional outcomes of autografts do not show significant differences compared with fresh autologous grafts. For decellularized nerve grafts, defect length is identified as an independent risk factor, and the internal microenvironment (delayed angiogenesis, Schwann cell senescence, and reduced T-cell infiltration) is considered a key factor limiting long-segment regeneration. Additionally, the decellularization process (whether chemical, physical, or supercritical CO2) affects the integrity of the extracellular matrix and the presence of immune residuals, which directly impacts axonal guidance and host integration. Common adverse events following autograft transplantation include donor site numbness, neuromas, and scarring. In contrast, adverse events associated with decellularized nerve graft transplantation may present as inflammatory reactions, excessive scar proliferation, and misalignment or reconnection of regenerating axons, which can lead to sensory–motor cross-innervation. To mitigate these issues, combining decellularized nerve grafts with autologous Schwann cells, mesenchymal stem cells, or induced pluripotent stem cell– derived cells may help bridge the gap with autografts. However, the fact that structural recovery does not necessarily lead to functional recovery needs further clarification. Future research should establish large animal models to replicate the limits of human regenerative capacity, use gene editing to enhance the phenotype and microenvironment of transplanted cells, and develop a mild combined decellularization process that maximizes the preservation of natural nerve grafts. Through multidimensional optimization, decellularized nerve grafts have the potential to ultimately replace autograft transplantation, enabling precise repair of individualized, long-segment, and complex nerve defects. Related Articles | Metrics

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Bridging autophagy and endolysosomal dysfunction: Role of bridging integrator 1 in Alzheimer’s disease Julia Duckhorn, Doo Kyung Kim, Yu-Wen Alvin Huang 2026, 21 (7):  2769-2786.  doi: 10.4103/NRR.NRR-D-25-00243 Abstract ( 31 )   PDF (1840KB) ( 163 )   Save Alzheimer’s disease is a devastating neurodegenerative disorder affecting millions worldwide, with current treatments offering only limited benefits. Central to emerging research is the role of autophagy and endolysosomal pathways, which are essential for clearing misfolded proteins and damaged organelles. Bridging integrator 1 (BIN1), traditionally recognized for its role in membrane remodeling and endocytosis, has recently emerged as a top genetic risk factor for Alzheimer’s disease, linking cellular clearance mechanisms to the development of toxic amyloid-beta plaques and tau tangles. In this review, we provide an accessible overview of how disruptions in autophagy and endolysosomal trafficking contribute to the neurodegeneration process in Alzheimer’s disease, positioning BIN1 as a central mediator within this complex network. Recent advances have shown that alterations in BIN1 expression and isoform distribution are associated with increased tau pathology and changes in amyloid-beta processing. Moreover, BIN1 appears to also influence synaptic transmission, neuroinflammation, and overall cellular homeostasis. The integration of recent findings not only deepens our understanding of Alzheimer’s disease pathology but also opens new avenues for the development of targeted treatments. This timely perspective underscores the potential of modulating BIN1 activity to enhance cellular clearance mechanisms and offers hope for more effective interventions for Alzheimer’s disease. Related Articles | Metrics

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Lipid metabolism, microglia, and stroke Lei Chen, Minmin Zhang, Wei Wei, Qiang Li, Lijun Wang, Ming Zhao, He Li, Hongye Xu, Pengfei Yang, Ping Zhang 2026, 21 (7):  2787-2809.  doi: 10.4103/NRR.NRR-D-24-01523 Abstract ( 57 )   PDF (1993KB) ( 37 )   Save Microglia, lipids, and their interaction are found to play important roles in post-stroke immunity. Microglia are sensitive to detect environment change in injured brain. Activated microglia undergo phenotypical remodeling and trigger complex signal cascades to regulate immune responses after stroke. Lipids including peripheral lipid metabolism and lipid droplet biogenesis are involved in the control of microglia functions, such as activation, phagocytosis, proliferation, and pro-inflammation. In this review, we explore new scope of microglia and lipids in immune regulation of stroke. Implication of peripheral lipid metabolism after stroke is mentioned and advances in microglia-lipid interaction are discussed. We give a special focus on how diet and gut microbiome influence neuroinflammation system via gut–brain axis, and how these processes associate with the risk and outcome of stroke. Moreover, we reviewed the therapeutic targets related to lipid metabolism and microglial modulation after stroke. These can provide a prospective strategy for more efficient and safer treatment for ischemic and hemorrhagic stroke. Related Articles | Metrics

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Sonic Hedgehog signaling in oligodendrogenesis, myelination, demyelinating diseases, and remyelination Miguel Marchena-Fernández, Cristina Sánchez-Camacho , Emma Muñoz-Sáez, Alba Macías-Castellano, Fernando de Castro Soubriet 2026, 21 (7):  2810-2811.  doi: 10.4103/NRR.NRR-D-25-00005 Abstract ( 33 )   PDF (1024KB) ( 17 )   Save The Hedgehog (HH) family includes Indian (IHH), Desert (DHH), and Sonic Hedgehog (SHH). Proteins of the HH family are distinguished by their function as morphogens, i.e., molecules that regulate the pattern of tissue development in accordance with concentration gradient. Data accumulated over the years clearly demonstrate that HH signaling is essential in myelination, particularly in the life cycle of the oligodendrocyte lineage. DHH is a key factor for Schwann cell function in the myelination of the peripheral nervous system and IHH is directly involved in the specification of oligodendrocyte precursor cells (OPCs) at least in the zebrafish. The most studied family member in central nervous system (CNS) myelination is SHH. SHH signaling has been identified as a crucial component in oligodendrocyte differentiation and remyelination (Russo et al., 2024). SHH is synthetized as a 46 kDa precursor protein which undergoes an autoproteolytic cleavage producing the excision of 19 kDa amino-terminal region (HH-N) and SHH carboxy-terminal polypeptide. The HH-N domain binds cholesterol and palmitic acid producing a functional signaling molecule. Related Articles | Metrics

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Cholinergic pathways in neural stem cell regulation and glioblastoma progression: Shared origins and mechanisms Moawiah M. Naffaa 2026, 21 (7):  2812-2813.  doi: 10.4103/NRR.NRR-D-25-00288 Abstract ( 28 )   PDF (528KB) ( 14 )   Save Neural stem cells (NSCs) and glioblastoma stem cells (GSCs) share a complex regulatory landscape in which cholinergic signaling plays a pivotal role in both neural development and tumor progression. While acetylcholine (ACh) regulates NSC quiescence and differentiation within neurogenic niches, glioblastoma cells exploit these pathways to enhance their adaptability and invasiveness. The involvement of muscarinic (M3) and nicotinic (α7) receptors in both cell types suggests that glioblastoma retains neural progenitor-like traits, contributing to its plasticity and resilience. This article explores the shared cholinergic mechanisms between NSCs and GSCs, highlighting their role in both neural development and glioblastoma progression. Related Articles | Metrics

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Astrocytic NLRP6 inflammasome: From protective sentinels to drivers of alcohol-induced neuroinflammation Seema Singh, Shilpa Buch, Palsamy Periyasamy 2026, 21 (7):  2814-2815.  doi: 10.4103/NRR.NRR-D-24-01620 Abstract ( 38 )   PDF (813KB) ( 20 )   Save The innate immune system of the central nervous system (CNS), long viewed as primarily microgliadriven, is now increasingly recognized to include astrocytes as active participants in neuroimmune signaling. Chronic alcohol exposure triggers oxidative stress, glial activation, and sustained inflammation, ultimately contributing to cognitive decline and neuronal injury. While microglial inflammasomes, particularly nucleotide-binding domain, leucinerich–containing family, pyrin domain–containing-3 (NLRP3), have garnered attention in alcohol-related neuroinflammation, the recent study by Singh et al. (2025) extends this paradigm by identifying a miR-339-regulated NLRP6 inflammasome response in human fetal astrocytes exposed to ethanol. Their findings shed light on a potential astrocytespecific inflammatory mechanism, but also raise key questions about its translational applicability (Figure 1). Specifically, the use of proliferating fetal astrocytes as a model system may better reflect mechanisms relevant to fetal alcohol spectrum disorders than adult alcohol use disorder (AUD). Furthermore, the focus on a single inflammasome axis overlooks the complex interplay among multiple innate immune sensors and their divergent roles across CNS cell types and species. In this Perspective, we critically examine the implications of the miR-339/NLRP6 axis in the broader landscape of astrocytic inflammasome research, discuss the limitations of the current model system, and highlight future directions for establishing NLRP6 as a viable therapeutic target for alcohol-induced neuroinflammation. Related Articles | Metrics

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Rethinking microglia from a circadian perspective in neuroimmunology: New insights Daniele Mattei 2026, 21 (7):  2816-2817.  doi: 10.4103/NRR.NRR-D-25-00157 Abstract ( 41 )   PDF (933KB) ( 12 )   Save Microglia cells are the resident innate immune cells of the central nervous system (CNS) (Paolicelli et al., 2022). They play a pivotal role in CNS development and in maintaining homeostasis during adulthood. Microglia are being extensively studied for their involvement in CNS disorders, ranging from autoimmune diseases such as multiple sclerosis to neurodegenerative and psychiatric conditions, as well as stroke and brain tumors (Paolicelli et al., 2022). To harness microglia in therapeutic development, we need to deepen our understanding of their intricate biology. Our knowledge of microglia biology has evolved significantly with technological advancements, leading to a progressive “rethinking” of microglia cells within the field. Initially viewed as static cells, we now understand microglia to be highly motile and constantly surveillant. Once thought to be a homogeneous population of CNS macrophages, microglia are now recognized to occupy a range of cellular states (Paolicelli et al., 2022). Importantly, emerging evidence highlights circadian and diurnal rhythms as key contributors to microglial immune reactivity, morphology, and functions such as phagocytosis (Gu et al., 2023; GuzmánRuiz et al., 2023; Jiao et al., 2024). Circadian rhythms refer to physiological oscillations dictated by the endogenous biological clock, while diurnal rhythms refer to physiological variations set by external light cues that function as Zeitgeber time (ZT, German word for time-giver), such as the lightdark cycle (Guzmán-Ruiz et al., 2023). Currently, most microglial studies do not account for these oscillations, which can significantly impact study design and data interpretation. This perspective article aims to discuss why implementing a circadian framework in preclinical research is essential for advancing our understanding of microglia cells in both physiology and disease. Related Articles | Metrics

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Gamma entrainment as a functional target in deep brain stimulation Bandy Chen 2026, 21 (7):  2818-2819.  doi: 10.4103/NRR.NRR-D-25-00510 Abstract ( 37 )   PDF (605KB) ( 11 )   Save Deep brain stimulation (DBS) is a neuromodulation tool that involves the delivery of electrical impulses to specific brain regions through implanted electrodes. The principle behind DBS is to modulate dysfunctional neural circuits without the need for permanent structural alterations to the brain. Initially developed as a treatment for movement disorders such as Parkinson’s disease (PD), DBS has expanded to encompass various neurological and psychiatric disorders. Until recently, DBS uses high-frequency electrical pulses to disrupt abnormal patterns of brain activity. Recent advances in neuroscience are shifting toward precision-based rhythm restoration with the goal of reinstating normal oscillatory patterns. Entrainment of brain activity within the gamma range (30–100 Hz), particularly around 40 Hz, has demonstrated potential in improving neurological disorders such as Alzheimer’s disease (AD) and PD (Deng et al., 2024). This represents a shift in the goal of DBS from silencing neural circuits to restoring physiological brain rhythms. Related Articles | Metrics

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Valosin-containing protein, neural proteopathies, and implications for neural regeneration Jae-Geun Lee, Eun-Ji Lee, Hoon Ryu, Jeong-Soo Lee 2026, 21 (7):  2820-2821.  doi: 10.4103/NRR.NRR-D-25-00442 Abstract ( 26 )   PDF (811KB) ( 12 )   Save Proteostasis, also known as protein homeostasis, is a tightly regulated cellular quality control process that ensures the balance of protein synthesis, folding, posttranslational modifications, and degradation. Maintaining proteostasis is vital for cellular function, organismal health, and longevity. The disruption of proteostasis can lead to a range of detrimental effects, including accelerated aging, compromised cellular function, and even cell death, manifesting in numerous human diseases (Hipp et al., 2019). Neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases (AD, PD, HD, respectively), are often characterized by the accumulation of misfolded proteins that aggregate into granules or inclusions. These aggregates form when proteins lose their proper conformation and fail to be refolded or degraded efficiently due to the failure of proteostasis. The persistence of these pathological protein aggregates can interfere with cellular processes, disrupt organelle function, and ultimately contribute to disease progression (Hipp et al., 2019). Related Articles | Metrics

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Mitochondria-derived vesicles in neurodegeneration Emanuele Marzetti, Riccardo Calvani, Hélio José Coelho-Júnior, Anna Picca 2026, 21 (7):  2822-2823.  doi: 10.4103/NRR.NRR-D-25-00305 Abstract ( 33 )   PDF (1735KB) ( 9 )   Save Mitophagy is a well-characterized and redundant recycling system for damaged mitochondria and a marker of organelle quality (Picca et al., 2023). Yet, the assessment of mitophagy in vivo remains a challenge. The characterization of the endosomallysosomal pathways supporting the endocytic trafficking has provided invaluable information also into mitophagy signaling. The endocytic pathway has been implicated in preserving mitochondrial quality via generation of mitochondria-derived vesicles (MDVs) and, as such, has been related to mitophagy tasks (Ferrucci et al., 2024). Altered mitophagy and MDV signaling accompany brain aging and neurodegenerative conditions (Ferrucci et al., 2024). However, how MDVs can be best characterized to be exploited as hallmarks of health and disease is debated. MDVs may be a trait d’union between dysfunctional mitophagy and decline of cell homeostasis through shuttling and/or being themselves mitochondriaderived damage-associated molecular patterns. These latter by instigating chronic low-grade inflammation may support neuroinflammation and neurodegeneration (Ferrucci et al., 2024). Alternatively, MDVs may rescue mitochondrial bioenergetics of neighbouring cells and favour neuronal health by transferring functional organelles. However, what defines one or the other role of MDVs and whether the outcome is mediated by vesicle subpopulations released under different metabolic triggers remain to be defined. Herein, we discuss MDVs as surrogate and more accessible measures of mitophagy. We also highlight the importance of addressing challenges in MDVs isolation and characterization to appreciate their signaling roles in neurodegeneration. Related Articles | Metrics

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Pathogenic landscape shaped by cerebral amyloid oligomers Yujing Huang , Mengze Xu , Zhen Yuan , Pu Chun Ke 2026, 21 (7):  2824-2825.  doi: 10.4103/NRR.NRR-D-25-00557 Abstract ( 27 )   PDF (993KB) ( 17 )   Save Amyloid oligomers, a brief history: Amyloid d i s e a s e s e n c o m p a s s a r a n g e o f h u m a n neurological, systemic, and metabolic disorders, characterized by the common feature of amyloid fibril and plaque deposition, either intracellularly or extracellularly. Among them, Alzheimer’s disease (AD)—manifested by memory loss and cognitive decline—and Parkinson’s disease (PD)— underlined by impaired dopamine release and motor dysfunction—are the two most prevalent forms of neurodegenerative conditions that have rapidly become global epidemics. Type 2 diabetes, conversely, is a prevalent metabolic disorder underpinned by pancreatic beta cell loss, elicited primarily by the aggregation and toxicity of human islet amyloid peptide. Related Articles | Metrics

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Rethinking dementia in the oldest old: Lessons to learn for the diagnosis and treatment of Alzheimer’s disease Chiara Giuseppina Bonomi, Caterina Motta, Martina Gaia Di Donna, Martina Poli, Giacomo Koch, Alessandro Martorana 2026, 21 (7):  2826-2827.  doi: 10.4103/NRR.NRR-D-25-00312 Abstract ( 30 )   PDF (623KB) ( 14 )   Save Dementia and Alzheimer’s disease (AD) are both age-related conditions that predominantly affect older adults. According to prevalence studies, the burden of these diseases on society is expected to increase in the coming years, particularly in relation to rising longevity and life expectancy. Advances in therapeutic and preventive strategies are needed to help reduce their global burden, which remains among the most significant health challenges in aging populations (Brookmeyer et al., 2007). Related Articles | Metrics

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Neural networks and econometric models: Advancing brain connectivity for Alzheimer’s drug development Lorenzo Pini , Paolo Pigato, Gloria Menegaz, Ilaria Boscolo Galazzo 2026, 21 (7):  2828-2829.  doi: 10.4103/NRR.NRR-D-25-00317 Abstract ( 31 )   PDF (2168KB) ( 34 )   Save Advances in Alzheimer’s disease (AD) research have deepened our understanding, yet the mechanisms driving its progression remain unclear. Although a range of in vivo biomarkers is now available (e.g., measurements of amyloidbeta (Aβ) and tau accumulation – the molecular hallmarks of AD – structural magnetic resonance imaging (MRI), assessments of brain metabolism, and, more recently, blood-based markers), a definitive diagnosis of AD continues to be challenging. For example, Frisoni et al. (2022) proposed a shift from a deterministic, amyloidcentered approach to a probabilistic framework that integrates genetic and environmental factors. Similarly, Dubois et al. (2024) cautioned against diagnosing AD based solely on molecular markers in cognitively normal individuals, advocating instead for the designation of “at risk” individuals. These perspectives reflect an evolving understanding of AD that is continuously reshaping both clinical and pharmacological approaches. Moreover, the recent approval of two diseasemodifying agents (Lecanemab and Donanemab) that target misfolded Aβ proteins has underscored significant limitations, particularly their moderate impact on clinical and cognitive outcomes. The discrepancy between the improvements in AD biomarkers with anti-Aβ drugs and their limited clinical benefits underscores the need for a new paradigm. In this context, assessing Aβ levels can be compared to measuring blood pressure: just as high blood pressure does not inevitably lead to cardiovascular disease, and some individuals with the disease may not have elevated blood pressure, the multifactorial nature of AD suggests that Aβ accumulation alone does not define the disease. Related Articles | Metrics

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Transcription factor NR2F1 is involved in Parkinson’s disease Annemarie de Vries, Silvia Bolognin 2026, 21 (7):  2830-2831.  doi: 10.4103/NRR.NRR-D-25-00290 Abstract ( 31 )   PDF (751KB) ( 19 )   Save Nuclear receptor subfamily 2 group F member 1 (NR2F1, also called COUP-TF1) is a transcription factor and part of the steroid/thyroid hormone receptor superfamily (Gay et al., 2002). NR2F1 is an orphan receptor that dimerizes to bind DNA and acts as a repressor as well as an activator of the target genes (Gay et al., 2002; Bertacchi et al., 2019; Bonzano et al., 2023). It was found recently to regulate the transcription of mitochondrial genes and to affect the morphology and mass of mitochondria (Bonzano et al., 2023). NR2F1 is mainly known for its pleiotropic role in neurodevelopment, but it has recently been connected to neurodegeneration in the context of Parkinson’s disease (PD) (Walter et al., 2021). This perspective summarizes the known functions of NR2F1 and offers a new perspective on its potential role in neurodegeneration. Related Articles | Metrics

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Antigen presentation at the brain barriers in multiple sclerosis Joshua Brands, Jeroen Bogie, Bieke Broux 2026, 21 (7):  2832-2833.  doi: 10.4103/NRR.NRR-D-25-00206 Abstract ( 35 )   PDF (2722KB) ( 13 )   Save Loss of immune tolerance to central nervous system (CNS) antigens lies at the heart of multiple sclerosis (MS), the most common chronic autoimmune disease of the CNS. MS affects nearly 2 million people worldwide and is characterized by focal areas of demyelination, inflammation, axonal injury, and neurodegeneration (Bronge et al., 2022; Magliozzi et al., 2023). The condition leads to symptoms such as numbness, muscle weakness, fatigue, visual impairment, and cognitive decline (Magliozzi et al., 2023). Although autoreactive T cells are considered to be primed in peripheral lymphoid tissues initially, it is the local reactivation of these T cells upon encountering CNS antigens that critically drives the inflammatory response within the CNS (Koch et al., 2022). It has become increasingly apparent that brain barriers, such as the blood–brain barrier (BBB), the blood– cerebrospinal fluid barrier (BCSFB), and the meninges, are central to modulating the immune response and driving MS pathology, potentially by facilitating antigen presentation and thus T cell reactivation (Ampie and McGavern, 2022; Magliozzi et al., 2023; Zierfuss et al., 2024). In this perspective, we examine current evidence on how antigen presentation occurs at major brain barrier sites and their contribution to triggering MS onset and progression. Related Articles | Metrics

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Proteostasis decline and endoplasmic reticulum stress in aging: Implications for cellular senescence and senescence-associated secretory phenotype regulation Philippe Pihán, Lisa M. Ellerby, Claudio Hetz 2026, 21 (7):  2834-2835.  doi: 10.4103/NRR.NRR-D-25-00161 Abstract ( 44 )   PDF (599KB) ( 22 )   Save Aging is a universal biological process characterized by the progressive decline in cellular and tissue function, representing the main risk factor for the development of most chronic human diseases. At the cellular level, one hallmark of aging is the accumulation of senescent cells—non-dividing yet metabolically active cells that adopt a unique phenotype, including the senescence-associated secretory phenotype (SASP) (Wang et al., 2024). The SASP encompasses a complex secretory program of bioactive molecules, including proinflammatory cytokines such as interleukin-6, interleukin-1 beta, and tumor necrosis factoralpha; chemokines such as CXC motif chemokine ligand 8/interleukin-8 and C-C motif chemokine ligand 2; growth factors such as vascular endothelial growth factor and hepatocyte growth factor; and matrix-remodeling enzymes such as matrix metalloproteinases. These factors influence the surrounding microenvironment by promoting inflammation, tissue remodeling, and paracrineinduced senescence. While the SASP may play a beneficial role in acute stress responses such as wound healing and tumor suppression, its chronic persistence contributes to systemic inflammation, stem cell exhaustion, and age-associated pathologies (Wang et al., 2024). Related Articles | Metrics

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Microglial CARD19 ameliorates post-stroke neuroinflammation by stabilizing mitochondrial cristae Yujie Hu, Liwen Zhu, Chao Zhou, Qi Li, Huiya Li, Shiji Deng, Shengnan Xia, Haiyan Yang, Xinyu Bao, Pinyi Liu, Yun Xu 2026, 21 (7):  2836-2848.  doi: 10.4103/NRR.NRR-D-24-00923 Abstract ( 49 )   PDF (7000KB) ( 23 )   Save Microglia are the first immune cells that are activated in the brain following ischemic stroke. Mitochondrial dysfunction exacerbates microglia-mediated neuroinflammation post-stroke. Caspase activation and recruitment domain 19 (CARD19) is involved in innate immune response and inflammatory response, which are also important functions of microglia. However, the role of CARD19 in microglial biology and ischemic stroke remains unknown. Here, we observed that CARD19 expression was significantly elevated in microglia in the penumbra after ischemic stroke via analyzing the spatial transcriptomic sequencing data of ischemic brain tissue, as well as in an in vitro model of microglial activation. Remarkably, conditional knockdown of Card19 in microglia promoted poststroke neuroinflammation and worsened neurological outcomes in a mouse model of ischemic stroke. Mechanistically, we found that CARD19 localized to mitochondria and promoted the assembly of mitochondrial intermembrane bridge components, while CARD19 deficiency in microglia caused ultrastructural and functional damage to the mitochondrial cristae, leading to an exaggerated pro-inflammatory response. Thus, our findings suggest that preserving mitochondrial cristae, by targeting CARD19 could be a novel therapeutic strategy for ameliorating neuroinflammation post-stroke and decreasing the volume of the ischemic penumbra. Related Articles | Metrics

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Chemerin 15 peptide reduces neuroinflammation via the ChemR23 receptor after ischemia–reperfusion injury Yan Huang, Shuang Li, Yuhan Yang, Kunyi Li , Lan Wen, Jinglun Li 2026, 21 (7):  2849-2860.  Abstract ( 30 )   PDF (10726KB) ( 10 )   Save Microglia-mediated neuroinflammation plays a crucial role in ischemic stroke; consequently, understanding its regulation could facilitate the development of therapies for ischemic stroke. Chemerin 15, a 15-amino acid peptide derived from chemerin, exerts powerful anti-inflammatory effects through ChemR23, modulates macrophage polarization, and diminishes inflammatory cytokine expression in peripheral inflammation models. However, its effects on microglia and stroke remain unclear. In this study, we used an in vitro oxygen/glucose deprivation BV2 cell model and a mouse model of ischemia-reperfusion injury to investigate the role of chemerin 15 in stroke and the underlying mechanisms. We co-cultured BV2 microglial cells with HT-22 hippocampal neurons and observed that chemerin 15 reduced apoptosis in HT-22 cells. Furthermore, we found that chemerin 15 binds to the ChemR23 receptor on the cell surface, inducing its internalization. This process regulated the activity of adenosine 5ʹ-monophosphate-activated protein kinase and inhibited its downstream target nuclear factor kappa B. These effects could be reversed by treatment with α-NETA, a ChemR23 inhibitor. In mice with ischemia-reperfusion injury, chemerin 15 modulated microglial polarization, reduced infarct volume and neuronal apoptosis, and facilitated cognitive and neurological function recovery. Our findings suggest that chemerin 15 suppresses the microglia-mediated inflammatory response, decreases neuronal apoptosis, and enhances long-term neurological function recovery by inducing ChemR23 internalization and regulating the adenosine 5ʹ-monophosphate-activated protein kinase/nuclear factor kappa B signaling pathway. Related Articles | Metrics

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Lycium barbarum glycopeptide reduces brain damage following ischemic stroke by inhibiting ferroptosis and oxidation Wei Zhang, Moushen Tang, Yujie Wang, Yongxia Huang, Zhexiong Yu, Lihui Zhu, Jian Wang, Kwok-Fai So, Yiwen Ruan 2026, 21 (7):  2861-2871.  Abstract ( 29 )   PDF (3754KB) ( 16 )   Save Recent studies have indicated that stroke can lead to neuronal iron overload and lipid peroxidation. Lycium barbarum glycopeptide, which has a low molecular weight and potent antioxidant properties, may mitigate ferroptosis in stroke. We hypothesized that Lycium barbarum glycopeptide can effectively mitigate iron overload within ischemic neurons due to its robust antioxidant properties. The aims of this study were to investigate the effects of Lycium barbarum glycopeptide on ferroptotic damage following brain ischemia and explore the underlying mechanisms. A rat model of middle cerebral artery occlusion was established using the intraluminal filament method, and the rats were treated with Lycium barbarum glycopeptide for 7 consecutive days, beginning 24 hours after ischemia. Liproxstatin-1, a ferroptosis inhibitor, and Erastin, a ferroptosis activator, were used as controls. We found that treatment with Lycium barbarum glycopeptide resulted in significant reductions in infarct volume (as detected by triphenyltetrazolium chloride staining staining and magnetic resonance imaging) and neuronal death (as measured by Nissl staining), as well as improvements in sensory and motor functions in rats subjected to middle cerebral artery occlusion. Furthermore, treatment with Lycium barbarum glycopeptide alleviated anxiety and depression-like behaviors and improved memory. Additionally, Lycium barbarum glycopeptide effectively reduced the iron ion content in the ischemic penumbra of the cortex. Moreover, treatment with Lycium barbarum glycopeptide downregulated the expression of ferroptotic and oxidant proteins such as transferrin receptor 1, divalent metal transporter 1, and Acyl-CoA synthetase long-chain family member 4 and upregulated the expression of anti-ferroptotic and antioxidant proteins such as ferroportin 1, solute carrier family 7 member 11, glutathione, and glutathione peroxidase 4. However, these beneficial effects were reversed when ferroptosis was induced with the activator Erastin. Therefore, the positive effects of Lycium barbarum glycopeptide in ischemic stroke are likely mediated through activation of the antiferroptotic pathway and the antioxidative System Xc-glutathione-glutathione peroxidase 4 pathway. Overall, our findings highlight the potential use of Lycium barbarum glycopeptide as a neuroprotective agent targeting both ferroptosis and oxidation to decrease ischemic brain damage. Related Articles | Metrics

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NeuroD1-based in situ neural regeneration for the treatment of radiation-induced brain injury Xudong Yan, Ke Zhong, Meijuan Zhou, Jiao Chen, Yajie Sun, Yamei Tang, Gong Chen, Yongteng Xu 2026, 21 (7):  2872-2883.  doi: 10.4103/NRR.NRR-D-24-01067 Abstract ( 36 )   PDF (46550KB) ( 15 )   Save Radiation-induced brain injury remains one of the most severe complications of radiotherapy for head and neck tumors, with limited options for prevention and treatment. In situ neural regeneration technology has demonstrated promising therapeutic effects in various neurodegenerative and neurotrauma conditions. In this study, we overexpressed the neural transcription factor NeuroD1 using in situ neural regeneration technology in a radiation-induced brain injury mouse model. This approach converted reactive astrocytes into neurons, increased neuronal density, protected endogenous neurons, decreased microglial activation, reduced peripheral CD8+ T cell infiltration, and diminished angiogenesis in the injured area, leading to a significant reduction in lesion volume. Additionally, we explored the potential mechanisms of NeuroD1 in situ neural regeneration technology through bulk RNA sequencing, which showed an upregulation of neurogenesis-related genes and a downregulation of immune response–related and angiogenesis-related genes. Furthermore, our findings suggested that NeuroD1 in situ neural regeneration technology converted reactive astrocytes into neurons and reduced microglial activation in a thalamic hemorrhagic stroke mouse model. In summary, this study supports NeuroD1 in situ neural regeneration technology as a potential therapeutic approach for treating radiationinduced brain injury and hemorrhagic stroke, and offers new insights into the therapeutic role of NeuroD1 in delayed brain injury. Related Articles | Metrics

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Comparative analysis of chemical and lentiviral approaches in the generation of human induced pluripotent stem cell–derived motor neurons Masood Sepehrimanesh, Wu Xu, Baojin Ding 2026, 21 (7):  2884-2892.  doi: 10.4103/NRR.NRR-D-24-00435 Abstract ( 43 )   PDF (1433KB) ( 20 )   Save The generation of human induced pluripotent stem cell–derived motor neurons overcomes limited access to human tissues and offers an unprecedented approach to modeling motor neuron diseases such as dystonia and amyotrophic lateral sclerosis. Motor neurons generated through different strategies may exhibit substantial differences in purity, maturation, characterization, and even neuronal identity, leading to variable outcomes in disease modeling and drug screening. However, very few comparative studies have been conducted to determine the similarities and differences among motor neurons prepared via different protocols. In this study, we prepared human induced pluripotent stem cell–derived motor neurons via lentiviral delivery of transcription factors and chemical induction and performed a systematic comparative analysis. We found that motor neurons generated by both approaches showed typical motor neuron morphology and robustly expressed motor neuron-specific markers, such as nuclear homeobox transcription factor 9 and choline acetyltransferase. The chemical induction protocol utilizes a combination of small molecules to induce motor neuron differentiation, offering a significantly faster maturation time of 35 days compared to 46 days with lentiviral delivery of transcription factors. Additionally, while lentiviral delivery of transcription factors are suitable for downstream biochemical analysis, chemical induction are more applicable for therapeutic approaches as they avoid the use of lentiviruses. Both approaches produce motor neurons with high purity (> 95%) and yield. No significant differences were found between chemical induction and lentiviral delivery of transcription factors in terms of motor neuron markers and maturation markers. These robust methodologies offer researchers powerful tools for investigating motor neuron diseases and potential therapeutic strategies. Related Articles | Metrics

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MDM2–GPX4–ferroptosis regulatory axis exerts neurotoxic effects in intracerebral hemorrhage Yunhu Yu, Tao Liu, Yunpeng Cai, Yuanmei Song, Hang Zhou , Fang Cao, Rongcai Jiang 2026, 21 (7):  2893-2903.  doi: 10.4103/NRR.NRR-D-25-00030 Abstract ( 35 )   PDF (3728KB) ( 10 )   Save Ferroptosis plays a key role in nerve injury in intracerebral hemorrhage and is associated with the upregulation of murine double minute 2. Investigating the mechanism underlying murine double minute 2-related ferroptosis could help identify new therapies for intracerebral hemorrhage. An in vitro intracerebral hemorrhage model was established by treating BV2 microglial cells with oxygen–glucose deprivation combined with hemin. The role of murine double minute 2 in regulating ferroptosis was investigated via transduction with RNA interference and lentivirus overexpression. Furthermore, intracerebral hemorrhage mouse models were constructed with and without an murine double minute 2 inhibitor (brigimadlin), and behavioral assays were performed to assess the learning ability and cognitive function. Murine double minute 2 dysregulation was associated with oxygen–glucose deprivation combined with hemin-induced BV2 microglial cell ferroptosis and M1/M2 polarization. The results suggested that murine double minute 2 induced glutathione peroxidase 4 ubiquitination and degradation to regulate ferroptosis and inflammatory responses in BV2 microglial cells. Mechanistically, Wilms tumor 1-associated protein induced murine double minute 2 N6-methyladenosine (m6A) modification and regulated ferroptosis and inflammatory responses. In vivo analysis showed that brigimadlin improved neurological deficits and spatial memory in mice with intracerebral hemorrhage. In summary, the results indicate that Wilms tumor 1-associated protein regulates murine double minute 2 m6A modification, and murine double minute 2 induces glutathione peroxidase 4 ubiquitination and degradation. This regulation promotes ferroptosis and inflammatory responses in oxygen–glucose deprivation combined with hemin-induced BV2 microglial cells, suggesting that the murine double minute 2–glutathione peroxidase 4–ferroptosis regulatory axis exerts neurotoxic effects. These findings identify glutathione peroxidase 4 as a potential gene therapy target for intracerebral hemorrhage–related brain injury. Related Articles | Metrics

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Impairment of hippocampal long-term potentiation by soluble amyloid-β oligomers is mediated by glutamate transporter 1 expressed in neurons Shaomin Li, Jianlin Wang , Qianqin Guo , Yunxin Bai , Wen Liu , Kevin J. Hodgetts , Paul A. Rosenberg , Dennis J. Selkoe 2026, 21 (7):  2904-2912.  doi: 10.4103/NRR.NRR-D-24-00882 Abstract ( 20 )   Save In Alzheimer’s disease, perturbations of glutamate neurotransmission lead to synaptic dysfunction and synapse loss. Several studies have used glutamate transport inhibitors to demonstrate that soluble oligomers of amyloid-β induce synaptic dysfunction by interrupting glutamate uptake mediated by glutamate transporter 1, the major glutamate transporter in the brain. The cellular targets of the synaptic effects of soluble amyloid-β oligomers, including the nature of any interaction with glutamate transporter 1, remain ill-defined. We have generated a conditional glutamate transporter 1 knockout mouse to investigate celltype specific functions of glutamate transporter 1. Field excitatory postsynaptic potentials were examined in the CA1 region of mouse hippocampal slices. We confirmed that hippocampal long-term potentiation impairment is induced by both soluble Aβ oligomers and glutamate uptake inhibitors. Amyloid-β oligomers, including those isolated directly from the cortex of patients with Alzheimer’s disease, failed to inhibit hippocampal long-term potentiation in neuronal glutamate transporter 1 but not astrocytic glutamate transporter 1 knockout mice. The masking or occlusion of the effect of soluble Aβ oligomers by knockout of glutamate transporter 1 in neurons suggests that the metabolic or signaling consequences of knockout of glutamate transporter 1 in neurons and oAβ inhibition of synaptic plasticity show epistasis and thus share a similar molecular pathway. To extend these observations, we tested the effects of other types of manipulation of glutamate homeostasis on synaptic plasticity and the pathophysiology of soluble Aβ oligomers. Ceftriaxone, which upregulates glutamate transporter 1 levels, among other effects, prevented the impairment of long-term potentiation by soluble Aβ oligomers. Collectively, our findings suggest that the effects of amyloid-β on synaptic function are highly dependent on glutamate reuptake homeostasis and that the disruption of synaptic function by soluble Aβ oligomers is mediated by pathways linked to neuronal, not astrocytic, glutamate transporter 1. This study’s findings highlight the translational potential of targeting neuronal glutamate transporter 1 to counteract amyloid-β-induced synaptic dysfunction in Alzheimer’s disease. By showing that glutamate transporter 1 upregulation (e.g., via ceftriaxone) can prevent Aβ-related impairments, this research supports developing therapies aimed at modulating glutamate homeostasis to preserve synaptic function and combat cognitive decline in patients with Alzheimer’s disease. Related Articles | Metrics