Experimental Neurology最新文献

{"title":"Corrigendum to \"Let-7d-5p improves mouse cognitive function by targeting bach1 in Alzheimer's disease\" [Exp. Neurol. 406 (2026) 115957; https://doi.org/10.1016/j.expneurol.2026.115957].","authors":"Yu Liu, Lang Peng, Ming Li, Wenjing Yan, Qingwei Xiang","doi":"10.1016/j.expneurol.2026.116016","DOIUrl":"10.1016/j.expneurol.2026.116016","url":null,"abstract":"","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"116016"},"PeriodicalIF":4.8,"publicationDate":"2027-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148911236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Mechanisms and precision intervention strategies of time-dependent dynamic regulation of matrix metalloproteinase-mediated cerebrovascular barrier disruption and neurovascular unit remodeling in stroke\" [Exp. Neurol. 407 (2026) 116039].","authors":"Peng Wang, Jia-Wei Wu, Bing-Xin Wang, Cui-Yan Chen, Chun-Lin Wu, Xiao-Fu Zhai, Xu-Dong Zhao","doi":"10.1016/j.expneurol.2026.116046","DOIUrl":"10.1016/j.expneurol.2026.116046","url":null,"abstract":"","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"116046"},"PeriodicalIF":4.8,"publicationDate":"2027-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effectiveness of exercise training on hippocampal mitochondrial regulation in Alzheimer's disease: A mechanistic systematic review.","authors":"Sean Kao, Farhan Yousaf, Shahid Ishaq, Iqbal Ali Shah, Bor-Tsang Wu, Shin-Da Lee","doi":"10.1016/j.expneurol.2026.116070","DOIUrl":"https://doi.org/10.1016/j.expneurol.2026.116070","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is associated with hippocampal mitochondrial dysfunction, including impaired mitophagy, biogenesis, dynamics, bioenergetics, and redox homeostasis, which may contribute to amyloid-β (Aβ) accumulation, tau pathology, and cognitive decline. This systematic review examined whether exercise training is associated with changes in hippocampal mitochondrial regulation and cognitive function in transgenic AD rodent models. Following PRISMA 2020 guidelines, PubMed, EMBASE, and Web of Science were searched up to July 2, 2026. Twenty-one studies met inclusion criteria. Exercise modalities included treadmill running, voluntary wheel running, and swimming, with durations from 4 weeks to 8 months. Risk of bias was assessed using the SYRCLE tool. Due to heterogeneity, meta-analysis was not appropriate; a narrative synthesis was performed. Exercise training was associated with changes in markers of mitophagy, biogenesis, dynamics, and function, as well as reduced oxidative stress, decreased Aβ and tau pathology, and improved spatial learning and memory. However, most studies assessed static markers rather than functional flux, and risk of bias was unclear in several domains. The evidence suggests that exercise training may be associated with hippocampal mitochondrial modulation and cognitive benefits in AD models, but conclusions are limited by heterogeneity and incomplete reporting. Further studies with functional mitochondrial assays and clear reporting of methods and results are needed.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"116070"},"PeriodicalIF":4.8,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-divergent neurovascular and cognitive effects of chronic cerebral hypoperfusion.","authors":"Brandon D Kirby, Briana L Clary, Emily Burrage, Paul D Chantler, Duaa Dakhlallah, Kate Karelina, Candice M Brown, James W Simpkins","doi":"10.1016/j.expneurol.2026.116066","DOIUrl":"https://doi.org/10.1016/j.expneurol.2026.116066","url":null,"abstract":"<p><p>Chronic cerebral hypoperfusion is the leading risk factor for the development of vascular dementia and is associated with white matter damage and cognitive impairment. Here, we assessed sex differences in vascular and neural pathology and cognitive impairment in the asymmetric carotid arterial stenosis (ACAS) mouse model of chronic cerebral hypoperfusion. Thirty days of ACAS significantly reduced cerebral blood flow, increased microvascular permeability as evidenced by extravasation of IgG and fibrinogen into brain parenchyma, and impaired MCA vasodilation. ACAS also induced white matter damage in the hippocampus and corpus callosum, with greater damage in the corpus callosum of females compared to males. Spatial memory impairments on the Barnes maze were significantly greater in ACAS males than in females. Finally, miRNA analyses revealed upregulated angiogenic miRNA in the hippocampus and cortex in ACAS females and upregulated neuroinflammatory miRNA in the hippocampus and cortex in ACAS males. Together, these findings indicate that the ACAS model produces robust neuropathology and sex differences in spatial memory and miRNA profiles.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"116066"},"PeriodicalIF":4.8,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel acylation modifications in cerebrovascular disease: Molecular mechanisms, crosstalk and therapeutic potential.","authors":"Yun Yong, Tao Liu, Meilong Si, Lincheng Yang, Xuan Bao, Haoming Luo, Chao Chai, Jin Hua","doi":"10.1016/j.expneurol.2026.116065","DOIUrl":"10.1016/j.expneurol.2026.116065","url":null,"abstract":"<p><p>Secondary injury in cerebrovascular disease involves energy failure, oxidative stress, neuroinflammation, blood-brain barrier disruption and neurovascular unit dysfunction. Novel lysine acylations, including lactylation, succinylation, beta-hydroxybutyrylation and crotonylation, have emerged as interfaces through which metabolic changes in lactate, succinate, ketone bodies and short-chain acyl-CoA species are translated into transcriptional regulation and altered protein function. This review organizes the evidence according to a framework that links metabolic donors, writer and eraser enzymes, modification sites, cell types and disease stages. We distinguish relatively developed experimental evidence in acute ischemic stroke and cerebral ischemia-reperfusion injury from limited findings in haemorrhage and predominantly exploratory evidence in chronic hypoperfusion and vascular cognitive impairment. Proteomic studies have identified 1003 lactylation sites across 469 proteins in rats subjected to cerebral ischemia-reperfusion injury, although most sites have not undergone causal validation. Comparatively strong evidence has accumulated for sites or regulatory axes involving MeCP2, SOD2, NEK7, ACSL4, PLBD1 and ZO-1. Collectively, current findings indicate that the effects of a given acylation cannot be inferred from its global abundance because they depend on substrate function, cellular origin and the therapeutic window. Major limitations include insufficient site-specific causal evidence, difficulty in directly quantifying crosstalk among post-translational modifications, poor correspondence between animal models and clinical heterogeneity and the absence of effective delivery systems and pharmacodynamic biomarkers. Future studies should integrate spatiotemporally resolved multi-omics, endogenous site editing, cell-specific models, measurable target engagement and independent clinical cohorts to evaluate whether selected acylation sites can progress from experimental candidates to independently validated clinical markers or intervention targets.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"116065"},"PeriodicalIF":4.8,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A critical mechanistic synthesis of PINK1-mediated mitophagy signaling and its therapeutic targeting in Parkinson's disease neurodegeneration.","authors":"Abida Khan, Talha Jawaid, Zia Ur Rehman, Mohammed Kanan Alshammari, Md Afroz Bakht, Faiyaz Shakeel, Mohammed Zawiah, Mohd Imran","doi":"10.1016/j.expneurol.2026.116078","DOIUrl":"10.1016/j.expneurol.2026.116078","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a progressive neurodegenerative disorder that is associated with loss of dopaminergic neurons, mitochondrial dysfunction and disruption of cellular homeostasis. PTEN-induced kinase 1 (PINK1) plays a crucial role in mitochondrial quality control by regulating mitophagy, mitochondrial dynamics, and calcium signaling to maintain neuronal bioenergetic homeostasis. This review critically evaluates the molecular pathways underlying PINK1-mediated mitochondrial integrity and the mechanisms by which loss-of-function mutations contribute to the pathogenesis of PD. Familial early-onset PD is strongly associated with pathogenic PINK1 mutations identified through genetic studies. Therapeutic approaches targeting the PINK1 pathway are examined, including adeno-associated virus (AAV)-based gene delivery, direct small-molecule PINK1 activation (MTK458), and indirect modulation of mitophagy and mitochondrial homeostasis by compounds such as curcumin, resveratrol, cannabidiol, gastrodin, and quercetin. Moreover, the complementary restoration of mitochondrial homeostasis through the modulation of downstream targets, such as transcription factor EB (TFEB) activation and BCL2-interacting protein 3-like (BNIP3L/NIX)-mediated mitophagy, is discussed as an indirect therapeutic strategy. Another important finding is that PD is a biologically and clinically heterogeneous disease that requires biomarker-directed and genotype-stratified therapeutic development. Finally, major translational issues are critically evaluated, including challenges related to blood-brain barrier penetration, target specificity, and long-term safety of mitochondrial modulators.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"116078"},"PeriodicalIF":4.8,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Post-traumatic epilepsy: An historical review from ancient observations to modern molecular mechanisms.","authors":"Severn B Churn","doi":"10.1016/j.expneurol.2026.116081","DOIUrl":"https://doi.org/10.1016/j.expneurol.2026.116081","url":null,"abstract":"<p><p>Post-traumatic epilepsy (PTE) represents a significant neurological complication of traumatic brain injury (TBI), accounting for approximately 5% of all epilepsies and 10-20% of structural/symptomatic epilepsies in population studies. This review traces the evolution of PTE research from ancient medical observations through 140+ years of modern scientific investigation, with emphasis on the historical, epidemiological and clinical-trial literature that established the field's current conceptual and diagnostic framework. Molecular and cellular mechanisms are introduced only briefly as a bridge to this historical narrative, as they are addressed in-depth elsewhere in this special issue. Thus, this review will focus upon the transition from purely observational studies in the late 19th century through epidemiological investigations of wartime injuries, the development of animal models, molecular mechanistic discoveries, and contemporary prevention trials. Recent meta-analytic data (2022-2025) indicate that modern-era severe TBI cohorts show higher long-term PTE incidence than older estimates suggested. Despite substantial progress, PTE remains largely unpreventable, representing a critical unmet medical need, though a maturing pipeline of biomarker-enriched antiepileptogenesis trials offers genuine hope for the coming decade.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"116081"},"PeriodicalIF":4.8,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intravenous administration of a PHP.eB vector overexpressing neuronal Caveolin-1 delays motor neuron and neuromuscular degeneration in a TDP-43 mouse model of ALS.","authors":"Vinh Ta, Jerica Ju, Kate Kurata, Michael Van, Elinor Wong, Kenneth Ohgi, Yessenia Magaña, Michael Castle, Shanshan Wang","doi":"10.1016/j.expneurol.2026.116069","DOIUrl":"10.1016/j.expneurol.2026.116069","url":null,"abstract":"<p><p>TDP-43 proteinopathy is observed in over 95% of ALS cases, yet effective disease-modifying therapies remain elusive. We previously showed that neuron-specific overexpression of caveolin-1 via SynCav1 extended survival and delayed neurodegeneration in an SOD1 mouse model of ALS. Here, we further assessed the effect of systemic delivery of AAV-PHP.eB-SynCav1 in TDP-43^A315T mice. At 24 weeks, SynCav1-treated mice showed preserved motor neuron (MN) morphology, maintained neuromuscular junction (NMJ) innervation, and normalized pathologically driven neurotrophic transcription in the spinal cord. Immunoblotting revealed that SynCav1 increased calcium-impermeable GluA2 in membrane lipid rafts of lumbar SC. However, these effects diminished with disease progression: by 32 weeks, lumbar MN loss and NMJ denervation were no longer significantly different between TDP-43-SynNull and TDP-43-SynCav1 mice, although partial protection was observed in the cervical spinal cord. These findings establish SynCav1 as an effective early-phase neuroprotective strategy and highlight the need for combinatorial approaches to achieve sustained protection.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"116069"},"PeriodicalIF":4.8,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activating systemic inflammation with lipopolysaccharide drives microglia-mediated degradation of perineuronal nets after cervical spinal cord injury in female rats.","authors":"Jaison Cucarian, Ram Rakheja, Kale R Scatterty, Edward Armstrong, Sydney Storvold, Antoinette T Nguyen, Keith Fenrich, Joshua E Burda, Steve Lacroix, Karim Fouad","doi":"10.1016/j.expneurol.2026.116068","DOIUrl":"https://doi.org/10.1016/j.expneurol.2026.116068","url":null,"abstract":"<p><p>Functional gains from rehabilitative motor training after spinal cord injury (SCI) depend on neuroplasticity, which naturally declines over time. We previously demonstrated that combining the pro-inflammatory compound lipopolysaccharide (LPS) with motor training reawakens neuroplasticity and enhances its therapeutic efficacy in chronic cervical SCI rats, though the underlying mechanisms remained unclear. Here, we investigated whether LPS-induced inflammation facilitates neuroplasticity by degrading perineuronal nets (PNNs), extracellular structures known to restrict recovery after SCI. Adult female Lewis rats received a single intraperitoneal LPS injection (1.5 mg/kg) ten days post-cervical SCI. In the first experiment, five days post-injection, we observed significantly diminished PNN marker fluorescence around ventral horn motor neurons in spared, injury-reactive spinal cord regions. To determine the cellular mechanism, we conducted a second experiment in which we pharmacologically attenuated microglial activity using minocycline (35 mg/kg). Minocycline treatment successfully prevented the LPS-induced loss of PNN fluorescence, demonstrating that microglia actively mediate PNN breakdown. Collectively, these findings provide a proof-of-concept mechanism by which inflammation influences neuroplasticity following central nervous system injury. Our observations support the growing recognition that inflammation, far from being exclusively detrimental, holds the capacity to contribute to healing after injury. By activating microglia to degrade PNNs, LPS-induced inflammation removes the structural barrier surrounding motor neurons, potentially priming them to be more responsive to the neuroplastic changes induced by rehabilitative motor training, providing a plausible explanation for our previously reported outcomes. This study highlights neuroimmune interactions as key regulators of neuroplasticity and the therapeutic efficacy of rehabilitative interventions in neurological disorders.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"116068"},"PeriodicalIF":4.8,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Constraint-induced movement therapy after ischemic stroke: From cortical reorganization to molecular plasticity","authors":"Bo Hyun Jung,&nbsp;Moo-Ho Won,&nbsp;Ki-Yeon Yoo,&nbsp;Sun Hong Song","doi":"10.1016/j.expneurol.2026.116053","DOIUrl":"10.1016/j.expneurol.2026.116053","url":null,"abstract":"<div><div>Stroke recovery is a dynamic, multilevel process involving structural, functional, and molecular reorganization of surviving neural circuits. Constraint-induced movement therapy (CIMT) has emerged as one of the most effective rehabilitation strategies for improving upper-limb motor function after stroke by overcoming learned nonuse and promoting activity-dependent plasticity. This review integrates clinical and experimental evidence to provide a comprehensive mechanistic framework of CIMT-induced recovery. At the systems level, motor recovery is governed by peri-infarct plasticity, diaschisis reversal, and behavioral adaptation within a temporally defined plasticity window. Experimental studies using middle cerebral artery occlusion (MCAO) models demonstrate that CIMT enhances synaptic remodeling, neurogenesis, angiogenesis, and neurovascular adaptation in peri-infarct regions. At the molecular level, CIMT engages coordinated signaling pathways, including brain-derived neurotrophic factor (BDNF)–TrkB signaling, synaptic structural proteins (GAP-43, synaptophysin, PSD-95), modulation of axonal growth inhibition via the Nogo-A/ROCK pathway, and regenerative processes that support neural circuit reorganization. Comparative analysis indicates that CIMT primarily drives task-specific cortical plasticity, whereas treadmill exercise promotes global neuroplasticity through neurotrophic and neurovascular mechanisms. Combined rehabilitation strategies integrate these complementary effects, leading to synergistic recovery across multiple functional domains. From a translational perspective, optimal rehabilitation likely requires a multimodal framework integrating task-specific, aerobic, and neuromodulatory interventions. Future research should focus on identifying biomarkers of responsiveness and defining optimal timing, intensity, and sequencing of therapies to enable personalized rehabilitation strategies.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"408 ","pages":"Article 116053"},"PeriodicalIF":4.8,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149166006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}