NeuroMolecular Medicine最新文献

{"title":"Rebalancing α-Synuclein Clearance: Novel Therapeutic Frontiers in Parkinson's Disease.","authors":"Maryam Jabeen, Huma Hameed, Syed Muhammad Ahmad, Tehreem Mushtaq, Mahtab Ahmad Khan, Anam Hameed","doi":"10.1007/s12017-026-08948-3","DOIUrl":"https://doi.org/10.1007/s12017-026-08948-3","url":null,"abstract":"<p><p>Parkinson's disease (PD), the second most common neurodegenerative condition, develops because of abnormal protein misfolding and aggregation of α-synuclein with its subsequent intercellular spread. Such pathological changes lead to disruption of neuronal homeostasis and contribute to neuronal degeneration. During normal conditions, α-synuclein clearance is controlled by different types of lysosomal degradation, namely, macro autophagy, chaperone-mediated autophagy (CMA), micro autophagy, and the ubiquitin-proteasome system. Malfunction of these systems results in increased α-synuclein secretion due to exosome-dependent, direct, and damage-induced mechanisms, which, in turn, promotes enhanced intercellular propagation, inflammation, mitochondrial dysfunction, blood-brain barrier leakage, and neuronal cell death. Although several approaches targeting α-synuclein clearance have shown biological activity in preclinical or early clinical studies, consistent disease-modifying efficacy has not yet been established, owing to challenges including target specificity, blood brain barrier penetration, biological heterogeneity, and the limited sensitivity of clinical endpoints. Recent research indicates that successful treatment is more related to restoring the balance of these two processes than to manipulating one of them.In this review, it is proposed that a systems-level approach can be taken where PD is understood as a disease characterized by the imbalance in proteostasis. Potential treatment modalities include small molecules targeting lysosome function (ambroxol, rapamycin, TFEB activators), CMA enhancers, gene therapy, and antibodies against extracellular α-synuclein. Furthermore, new modalities like molecular glue degraders, allostery-based stabilization of α-synuclein tetramers, engineered decoy particles, and bispecific antibodies represent some other possible routes towards multimodal disease modification.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148866026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AMBMP Hydrochloride Reverses STZ-Induced Alzheimer-Type Dementia Associated with Wnt/β-catenin/TLR4 Signaling.","authors":"Palak Kalra, Deepak Chaturvedi, Amit Kumar, Amarjot Kaur Grewal, Heena Khan, Varinder Singh, Thakur Gurjeet Singh, Tanveer Singh, Sheikh F Ahmad, Sabry M Attia","doi":"10.1007/s12017-026-08947-4","DOIUrl":"https://doi.org/10.1007/s12017-026-08947-4","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a debilitating neurodegenerative disorder with progressive cognitive decline and neuronal loss. This study investigated the neuroprotective effects of AMBMP Hydrochloride, a Wnt/β-catenin agonist, in a streptozotocin (STZ)-induced mice model of AD, elucidating the interplay between dysregulated Wnt/β-catenin signaling and Toll-Like Receptor 4 (TLR4)-mediated inflammation, with Palmitic acid used as a TLR4 pathway modulator. Mice received bilateral intracerebroventricular (i.c.v.) injections of STZ (3 mg/kg) on Day 1 and Day 3, followed by administration of Donepezil (3 mg/kg)/ AMBMP Hydrochloride (5 mg/kg and 10 mg/kg)/Palmitic acid (TLR4 agonist, 20 mg/kg) via the intraperitoneal (i.p.) route from Day 4 to Day 22. STZ-treated mice exhibited significant cognitive dysfunction, characterized by impaired performance in the Morris Water Maze (MWM) task along with increase in acetylcholinesterase (AChE) activity, oxidative stress (thiobarbituric acid reactive substances; TBARS), neuroinflammation [tumor necrosis factor alpha (TNF-α)/Interleukin-6 (IL-6)/Interleukin-1 beta (IL-1β) and nuclear factor kappa B (NF-κB)] and decreased reduced glutathione (GSH) levels. However, AMBMP Hydrochloride significantly improved behavioral and biochemical alterations possibly through modulation of Wnt/β-catenin signaling and attenuation of TLR4-mediated inflammation. Interestingly, Palmitic acid co-treatment was found to counteract these protective effects, further pointing to a role of TLR4 in the pharmacological effect of AMBMP Hydrochloride. In summary, we confirmed that AMBMP Hydrochloride exhibits potent neuroprotective effects associated with modulating Wnt/β-catenin/TLR4 signaling, offering a promising therapeutic approach against Alzheimer-Type Dementia. Future studies should delve deeper into the molecular mechanisms and translational promise of AMBMP hydrochloride, paving the way for its development as a potential candidate for AD management.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148857483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction Note: Thymoquinone and Vitamin C Attenuates Pentylenetetrazole-Induced Seizures Via Activation of GABA_B1 Receptor in Adult Rats Cortex and Hippocampus.","authors":"Ikram Ullah, Haroon Badshah, Muhammad Imran Naseer, Hae Young Lee, Myeong Ok Kim","doi":"10.1007/s12017-026-08946-5","DOIUrl":"https://doi.org/10.1007/s12017-026-08946-5","url":null,"abstract":"","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148818865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Semaglutide Alleviates LPS-Induced Cognitive Disorder via O-GlcNAcylation of AKT-mTOR Signaling Pathway Components.","authors":"Qiangwei Liu, Lu Chen, Mengxue Zhang, Zhun Wang, Xiaokun Wang, Ying Dong, Kaiyuan Wang, Changyu Jiang, Yiqing Yin","doi":"10.1007/s12017-026-08945-6","DOIUrl":"https://doi.org/10.1007/s12017-026-08945-6","url":null,"abstract":"<p><p>Perioperative neurocognitive disorder (PND) manifests as neurocognitive alterations induced by anesthesia and surgical stress. High-risk factors, including advanced age, obesity, diabetes, and preoperative neurological dysfunction, accelerate PND progression, with neuroinflammation serving as a core pathological mechanism throughout PND pathogenesis. Semaglutide regulates neuroinflammation in patients with diabetes and stroke, yet its role in PND remains undefined.A lipopolysaccharide (LPS)-induced inflammatory neurocognitive impairment mouse model was established via intracerebroventricular injection. Mice were treated with semaglutide alone or combined with the O-GlcNAc transferase inhibitor OSMI-1 and AKT-silencing adeno-associated viruses. Behavioral, biochemical and immunofluorescence assays were performed to evaluate cognitive function and molecular changes. Semaglutide significantly rescued LPS-induced cognitive deficits and restored hippocampal O-GlcNAcylation. Mechanistically, LPS inhibited AKT O-GlcNAc modification and AKT-mTOR pathway activity, facilitated mTOR-gephyrin binding, disrupted GABAAR distribution, aggravated neuronal apoptosis, and impaired synaptic plasticity. Semaglutide reversed these abnormalities by elevating AKT O-GlcNAcylation to activate the AKT-mTOR pathway, which triggered mTOR-gephyrin dissociation, restored synaptic GABAAR localization, attenuated neuronal damage, and rescued synaptic plasticity.Semaglutide ameliorates PND via AKT O-GlcNAcylation-mediated AKT-mTOR activation and subsequent neuroprotective effects.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148796090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Celiac Disease and the Nervous System: A Comprehensive Overview of Neurological Manifestations and Underlying Mechanisms.","authors":"Arash Yousefzadeh Eshkoori, Mohadeseh Mahmoudi Ghehsareh, Nastaran Asri, Somayeh Jahani-Sherafat, Mostafa Rezaei Tavirani, Alireza Zali, Masiha Amiri, Amirhosein Monazami, Mohammad Rostami-Nejad","doi":"10.1007/s12017-026-08940-x","DOIUrl":"https://doi.org/10.1007/s12017-026-08940-x","url":null,"abstract":"<p><p>Celiac disease (CD) is a chronic immune-mediated enteropathy triggered by gluten ingestion in genetically susceptible individuals. While traditionally associated with gastrointestinal (GI) symptoms, CD is increasingly recognized as a systemic disorder with significant neurological involvement. A growing body of evidence links CD to a broad spectrum of neurological manifestations, including gluten ataxia (GA), peripheral neuropathy (PN), epilepsy, migraine, myoclonic disorders, and cognitive impairment. These symptoms may precede or occur independently of GI symptoms, complicating diagnosis and delaying treatment. The underlying mechanisms are multifactorial, involving autoantibody cross-reactivity, neuroinflammation, increased permeability of the intestinal and blood-brain barrier (BBB), gut dysbiosis, and micronutrient deficiencies. This review synthesizes current insights into the pathophysiological basis of CD-related neurological disorders. We also explore the therapeutic impact of a strict gluten-free diet (GFD) on CD-related neurological manifestations. Early recognition of neurological signs and their prompt management are essential to mitigate irreversible neural injury and improve long-term outcomes in these patients. Given the potential for symptom reversibility with dietary treatment, routine screening for CD should be considered in patients presenting with idiopathic neurological syndromes, even in the absence of GI symptoms.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148707281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research Progress on Regulating Neuroinflammation After Spinal Cord Injury by Targeting the cGAS-STING Pathway.","authors":"Nanjian Xu, Weihu Ma, Weixin Dong, Liang Yu","doi":"10.1007/s12017-026-08938-5","DOIUrl":"https://doi.org/10.1007/s12017-026-08938-5","url":null,"abstract":"<p><p>Neuroinflammation following secondary injury in spinal cord injury (SCI) constitutes a major obstacle to functional recovery. Endogenous danger signals, particularly mitochondrial DNA (mtDNA) released post-injury, can activate the cGAS-STING pathway, thereby modulating the activation state of microglia and macrophages toward a pro-inflammatory phenotype. This process unfolds within a highly interconnected network involving Toll-like receptor (TLR) signaling, reactive oxygen species (ROS), NLRP3 inflammasome assembly, and cytokine cascades. Through crosstalk with the NLRP3 inflammasome, the cGAS-STING pathway can enhance cellular susceptibility to pyroptosis. The ultimate execution of pyroptotic cell death remains contingent upon additional downstream events, including the activation of Caspase-1 and the cleavage of Gasdermin D. The state of microglia and macrophages is dynamically regulated by a convergence of multiple signaling pathways. Furthermore, the cGAS-STING pathway engages in complex bidirectional interactions with autophagy, underscoring its multifaceted regulatory functions. This review explores emerging intervention strategies targeting this pathway, including small-molecule inhibitors/agonists, genetic interventions, and smart nanomaterials, aimed at achieving precise immunomodulation within the neuroimmune microenvironment. However, the clinical translation of this field still faces significant challenges, primarily concerning issues of spatiotemporal-specific modulation, drug delivery efficiency, and interspecies differences. Future research should focus on elucidating these intricate mechanisms and developing advanced drug delivery systems to facilitate the translation of this therapeutic target from a conceptual framework into clinically effective treatment modalities.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148630850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LncRNA DLX6-AS1 Regulates the Pathological Process Related to Alzheimer's Disease via miR-204-5p.","authors":"Minggang Jiang, Yang Lin, Liping Wang, Kaiyun Ou","doi":"10.1007/s12017-026-08941-w","DOIUrl":"https://doi.org/10.1007/s12017-026-08941-w","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative disorder causing progressive neuronal damage. Incidence rises with age, and early diagnosis is difficult. This study examined DLX6-AS1 clinical relevance and regulatory mechanism in AD, and its interaction with miR-204-5p in AD pathology. It offers new insights into early diagnosis and treatment. A total of 133 AD patients and 105 healthy controls were selected. Their serum levels of DLX6-AS1 and miR-204-5p were analyzed using quantitative polymerase chain reaction. β-amyloid (Aβ)_1-42-induced SH-SY5Y neuronal injury and okadaic acid (OA)-induced Neuro-2a tau abnormal phosphorylation models were constructed. The role/function of DLX6-AS1/miR-204-5p axis was then investigated using cell counting kit-8, flow cytometry, western blotting, enzyme-linked immunosorbent assay and a dual-luciferase reporter gene assay. AD patients had higher serum DLX6-AS1 and lower miR-204-5p levels. DLX6-AS1 showed an AUC of 0.838 for AD diagnosis. DLX6-AS1 levels were negatively associated with cognitive function, brain structural integrity, and benign pathology-and positively associated with disease severity, functional impairment, and pathological markers. In AD cell models, DLX6-AS1 was upregulated. Silencing it promoted cell proliferation, reduced apoptosis and oxidative stress, improved mitochondrial and synaptic function, decreased tau phosphorylation, and enhanced microtubule stability and axonal transport. Dual-luciferase assays confirmed direct binding between DLX6-AS1 and miR-204-5p. Co-inhibition reversed the protective effects of DLX6-AS1 silencing. Serum DLX6-AS1 is a potential biomarker for early diagnosis and assessment of AD. It regulates Aβ-induced neuronal damage and tau phosphorylation by targeting miR-204-5p, offering a new mechanism target for AD molecular therapy.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemogenetic Activation of Neurons Promotes Axonal Regeneration and Ameliorates Neurological Deficits in Mice with Intracerebral Hemorrhage by Modulating Mitochondrial Function.","authors":"Jinpeng Wang, Li Zhou, Chunxiao Pang, Hui Liu, Yongli Wang, Zengwu Wang, Wenyuan Ling","doi":"10.1007/s12017-026-08942-9","DOIUrl":"https://doi.org/10.1007/s12017-026-08942-9","url":null,"abstract":"<p><p>Intracerebral hemorrhage (ICH) is a devastating neurological condition characterized by high morbidity and mortality, with limited treatment options for promoting neurological recovery. Enhancing cortical excitability has emerged as a potential strategy for promoting neurological recovery. However, the role of neuronal activation in mitochondrial regulation and axonal regeneration after ICH remains unclear. A chemogenetic approach using adeno-associated virus (AAV)-human M3 muscarinic designer receptor exclusively activated by designer drugs (hM3Dq) was employed to selectively activate cortical excitatory neurons in an ICH mouse model. Behavioral assessments, histological analyses, and molecular evaluations of mitochondrial function and axonal integrity were performed. In vitro, PC12 cells were transfected with hM3Dq and subjected to Hemin-induced injury to assess mitochondrial dynamics and neurite outgrowth. Dynamin-related protein 1 (DRP1) overexpression was used to investigate the role of mitochondrial fission in hM3Dq-mediated effects. hM3Dq activation significantly improved motor and cognitive functions in ICH mice, reduced neuronal apoptosis, and enhanced axonal regeneration. These effects were associated with restored mitochondrial membrane potential, reduced oxidative stress, increased adenosine triphosphate (ATP) production, and partially restored mitochondrial dynamics-related protein expression. In vitro, hM3Dq overexpression mitigated mitochondrial dysfunction and promoted neurite elongation in PC12 cells. Importantly, DRP1 overexpression reversed these beneficial effects, suggesting that inhibition of mitochondrial fission is critical for hM3Dq-mediated neuroprotection. Chemogenetic activation of cortical neurons promotes neurological recovery after ICH and is associated with improved mitochondrial function and enhanced axonal regeneration. Modulation of DRP1-related mitochondrial fission signaling may partially contribute to these effects, suggesting a potential neuron-mitochondria interaction that may serve as a therapeutic target for hemorrhagic stroke.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148592580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sleep Duration and Epilepsy Risk: Mendelian Randomization and Functional Validation of CACNA1A rs2228130-Related Inhibitory Synaptic Dysfunction.","authors":"Xun Li, Yuying Hou, Yanping Ren, Wei Yue","doi":"10.1007/s12017-026-08943-8","DOIUrl":"https://doi.org/10.1007/s12017-026-08943-8","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Objectives To evaluate the causal association between sleep traits and epilepsy risk using Mendelian randomization, and to investigate the mechanism of a prioritized epilepsy-risk variant through gene-level enrichment analysis and functional validation. Methods Large-scale European GWAS datasets were analysed using multiple Mendelian randomization methods, including inverse variance weighted, MR-Egger and weighted median models, with heterogeneity and sensitivity analyses. Epilepsy-associated loci were mapped to protein-coding genes and flanking regions based on GRCh37 annotation, and primary and sensitivity-analysis gene sets were constructed from gene-level summary results for functional enrichment analysis. Guided by locus-level prioritization and the biological plausibility of CACNA1A, rs2228130 was selected for functional validation in CRISPR-ABE-edited human iPSC and knock-in mouse models to assess inhibitory synaptic transmission, sleep-related phenotypes and seizure susceptibility. Results Longer sleep duration was significantly associated with lower epilepsy risk (OR = 0.9937, p &lt; 1 × 10⁻⁵), supporting a protective genetic causal association. The association between insomnia and epilepsy showed substantial heterogeneity (Q = 9352.91) and should be interpreted cautiously. Gene-level enrichment analysis indicated that epilepsy-associated candidate genes converged primarily on broad biological regulation, developmental processes and multicellular organismal processes, without stable dominant enrichment of GABAergic synapse or circadian rhythm pathways. Functional validation showed that rs2228130 did not affect neuronal differentiation but impaired inhibitory synaptic transmission, accompanied by abnormal network activity, altered sleep-related phenotypes and increased seizure susceptibility. Knock-in mice exhibited more frequent epileptiform discharges, reduced non-rapid eye movement sleep, decreased slow-wave activity and altered expression of rhythm-related genes. Pharmacological and sleep-related interventions partially ameliorated these abnormalities. Significance This study supports a protective genetic causal association between longer sleep duration and lower epilepsy risk, and suggests that epilepsy-related genetic risk converges primarily on broad functional networks. Within this framework, functional validation of CACNA1A rs2228130 identifies inhibitory synaptic dysfunction as a key mechanistic node linking genetic risk to sleep- and epilepsy-related phenotypes, providing a rationale for epilepsy prevention and treatment through sleep optimization and targeted modulation of critical downstream pathways. Plain Language Summary We used large-scale genetic data and experimental models to examine how sleep is related to epilepsy. Genetic evidence showed that longer sleep duration was associated with lower epilepsy risk. Although broad gene-level analyses did not identify a stable dominant signal for GABAergic synapse or circadia","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STAT6 Targets the Autophagy Pathway to Regulate Microglial Senescence in Cognitive Impairment Caused by Cerebral Small-Vessel Disease.","authors":"Xiaolu Liu, Qing Liu, Jingwen Yang, Xia Hu, Xiaoqiu Zhu, Zhan Zhang, You Zuo, Jialin Huang, Lele Wu, Yuhua Fan, Yamei Tang, Zhongshan Shi","doi":"10.1007/s12017-026-08944-7","DOIUrl":"https://doi.org/10.1007/s12017-026-08944-7","url":null,"abstract":"<p><p>Cerebral small-vessel disease (CSVD) represents a major etiology of vascular cognitive impairment (VCI), driven by pathological processes such as cellular senescence and neuroinflammation. Among these, microglia-the brain's specialized immune cells-play a key role in driving neuroinflammation through their senescence, thereby exacerbating cognitive dysfunction. Although signal transducer and activator of transcription 6 (STAT6) activation has been implicated in alleviating neuroinflammation and cognitive deficits in CSVD, the underlying mechanisms remain unclear. This study sought to elucidate the roles of STAT6 and autophagy in the process of microglial senescence induced by CSVD. Using stroke-prone renovascular hypertensive rats (RHRSP) and chronic hypoxia-treated BV2 cells to assess cognitive function, microglial senescence, and autophagy, we observed that phosphorylation-mediated STAT6 activation significantly suppressed microglial senescence. Mechanistically, we found that phosphorylated STAT6 (pSTAT6) enhanced autophagy, which reduced the burden of senescent microglia and thereby ameliorated CSVD-induced VCI. These findings provide insights into the potential of targeting the STAT6 pathway in VCI associated with CSVD.</p>","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"28 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148472052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}