Molecular Neurobiology最新文献

{"title":"Glycogen Synthase Kinase-3β Mediates Suppression of Neurite Outgrowth Through Sonic Hedgehog Signalling in Palmitic Acid-Exposed Neuro2A Cells.","authors":"Pooja Singh, Shonak Vrujlal Ambaliya, Gajjar Shivam Kumar, Shreyash Santosh Yadav, Ashok Kumar Datusalia","doi":"10.1007/s12035-026-05916-7","DOIUrl":"https://doi.org/10.1007/s12035-026-05916-7","url":null,"abstract":"<p><p>Metabolic stress induced by saturated fatty acids such as palmitic acid (PA) disrupts key signalling pathways involved in neuronal survival, differentiation, and plasticity. The Sonic Hedgehog (Shh) pathway, essential for neurogenesis and tissue regeneration, is particularly vulnerable to PA-mediated suppression. In this study, we investigated the therapeutic potential of purmorphamine, a smoothened (SMO) agonist, and lithium chloride (LiCl), a GSK3β inhibitor, in restoring metabolic stress-induced insulin resistance and Shh signalling in Neuro2A cells. For the induction of insulin resistance or metabolic stress model, N2a cells were treated with PA (200 μM) for 24 h and validated by stimulation with insulin (100 nM) for various time periods 0, 5, 15, 30, 60, and 120 min. A blunted response was observed on pAKT^S473 and pGSK3β^S9 levels, indicating the development of insulin resistance. Cells were co-treated with purmorphamine (1 μM) or LiCl (10 µM) for 24 h alongside PA. PA exposure downregulated Shh components (PTCH1, SMO, Gli1) and transcriptional regulators (CREB, FOXO3), which further leads to reduced expression of neuroplasticity markers (BDNF, profilin1, SOX2) and compromised neurite outgrowth. Co-treatment with purmorphamine or LiCl significantly rescued these deficits, reinstating pathway activity and cellular function. Purmorphamine or LiCl also improved neurite outgrowth and restored the proliferative capacity of N2a cells. These findings highlight the role of GSK-3β and SMO signalling interactions in maintaining neuronal outgrowth and neuroplasticity.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147864141","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":"Integration of Metabolic Pathways and Micronutrient Signals Influences Neurodevelopment by Modulating Neural Stem Cell Dynamics.","authors":"Sayed Chandini, Debangana Dey, Tina Gulati, Amit Mishra, Yogita K Adlakha","doi":"10.1007/s12035-026-05904-x","DOIUrl":"https://doi.org/10.1007/s12035-026-05904-x","url":null,"abstract":"<p><p>Central nervous system (CNS) development commences in third week of gestation with neural stem cells (NSCs), which, through symmetric division, expand the pool of stem cells and generate diverse types of neuronal and glia cells of CNS via asymmetric division. During neurodevelopment, spatiotemporal coordination is fundamental for appropriate morphogenesis and producing neuronal connections. Besides gene regulatory networks, external and internal factors guide NSCs during self-renewal, fate determination and differentiation. Recent studies indicate metabolism as one of the common converging integrators in NSCs to trigger modifications in response to external factors. One such external factor is micronutrients that profoundly affect different stages of neurodevelopment, including, differentiation, neural migration and maturation. This review aims to provide a summary of recent insights into how metabolism and micronutrients regulate different events of neurodevelopment including proliferation, fate determination and differentiation. Notably, we focus on illustrating the implications of mitochondria as key determinants of NSC fate and functionality. We also highlight the recent development on how metabolism orchestrates the epigenome of NSCs during proliferation and differentiation. We further explore the role of nutraceuticals in mitigating the risk of neurodevelopmental and adult neurological disorders, highlighting recent innovations in their therapeutic applications. An in-depth grasp of these molecular processes is fundamental to improving translational strategies for treating neurological disorders.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840000","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":"Mitochondrial Gene Signature Reveals Novel Diagnostic Biomarkers for Autism Spectrum Disorder.","authors":"Jieyu Wang, Zeyu Cheng, Mingyuan Liu, Yuting Zhang, Yi Jiang, Tianyu Liu, Junyu Ren, Lijie Wu, Mingyang Zou, Caihong Sun","doi":"10.1007/s12035-026-05911-y","DOIUrl":"https://doi.org/10.1007/s12035-026-05911-y","url":null,"abstract":"<p><p>Autism Spectrum Disorder (ASD) pathogenesis remains unclear, with mitochondrial dysfunction implicated as a key contributor. Reliable mitochondrial-related diagnostic biomarkers are lacking, hindering early detection and mechanistic studies. This study integrated transcriptomic data from postmortem ASD cortical tissues (GSE28521 for training; GSE64018 for validation) with mitochondrial-related genes (MRGs) from MitoCarta3.0. Mitochondrial pathways were investigated using gene set enrichment analysis (GSEA). Candidate ASD-mitochondria (ASD-MIT) genes were identified by combining differential expression analysis, weighted gene co-expression network analysis (WGCNA), and MRGs. Machine learning algorithms (LASSO, Random Forest, and SVM-RFE) were applied to screen hub genes. Diagnostic performance was evaluated using a linear predictive model, an artificial neural network (ANN), and a nomogram. Single-sample GSEA (ssGSEA) was used to assess associations between hub genes and mitochondrial pathway activity. Biological validation included qPCR in BTBR mice and protein localization analysis using the Human Protein Atlas (HPA). GSEA revealed significant downregulation of mitochondrial pathways in ASD. 22 candidate ASD-MIT genes were identified, from which three hub genes-IDH3A, MRPL2, and CHCHD4-were consistently selected by all three machine learning models. The three-gene panel demonstrated strong diagnostic ability (AUC = 0.910), confirmed by the ANN model (AUC = 0.903). The nomogram achieved excellent predictive accuracy (C-index = 0.964). Importantly, ssGSEA analysis showed that these genes were strongly associated with mitochondrial pathway activity, particularly mitochondrial calcium ion transport. qPCR validated significant downregulation of Idh3a and Mrpl2 in BTBR mice, and HPA confirmed mitochondrial localization and brain expression. This study identifies a mitochondrial gene signature associated with ASD and highlights IDH3A, MRPL2, and CHCHD4 as promising diagnostic biomarkers. These findings advance understanding of mitochondrial dysfunction in ASD pathogenesis and further suggest that disruption of mitochondrial Ca²⁺-energy coupling may represent a key mechanistic feature of the disease.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840111","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":"NSUN6-Mediated m5C Modification of OAS2 Is Implicated in Neuronal PANoptosis during Perioperative Neurocognitive Disorders.","authors":"Xinhao Gong, Wen Liu, Hanqing Luo, Runna A, Yulong Hu, Yingchuan Hu, Xiaojin Feng, Shoulin Chen","doi":"10.1007/s12035-026-05770-7","DOIUrl":"https://doi.org/10.1007/s12035-026-05770-7","url":null,"abstract":"<p><p>Perioperative neurocognitive disorders (PND) are common in elderly patients, with emerging evidence linking their pathogenesis to abnormal cell death. PANoptosis is a newly identified inflammatory form of programmed cell death, but its role in PND remains unknown. Here, we employed animal behavioral tests, single-cell sequencing (scRNA-seq), methylated RNA immunoprecipitation-sequencing (meRIP-seq), RNA sequencing (RNA-seq), immunofluorescence, and TUNEL staining to investigate the role and underlying mechanisms of PANoptosis in PND. Y-maze and open-field experiments confirmed cognitive and locomotor deficits in a PND mouse model. scRNA-seq revealed altered cellular composition and neuronal heterogeneity in PND brain tissues, with elevated PANoptosis-related gene expression and scores in PND neurons. In vivo and in vitro assays confirmed increased expression of PANoptosis markers (ASC, AIM2, Pyrin) and neuronal apoptosis in PND. Based on the differentially expression gene (DEG) analysis conducted using scRNA-seq, we identified NSUN6 as a key gene that was significantly downregulated in neurons of the PND group, and overexpression of NSUN6 suppressed isoflurane-induced neuronal PANoptosis. RNA-seq and meRIP-seq further revealed that NSUN6 promoted m5C modifications enriched in CDSs and 3' UTRs, with pathway analysis implicating PANoptosis-associated signaling. OAS2 was identified as a direct substrate of NSUN6-mediated m5C modification, with NSUN6 overexpression enhancing both its m5C enrichment and expression. Collectively, our findings suggest that NSUN6 may be involved in OAS2-associated m5C modification and neuronal PANoptosis, supporting a potential role for the NSUN6/OAS2 axis in the pathogenesis of PND.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840128","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":"Advancements in Gene Delivery using Nucleic Acid Loaded Nanoparticles for Region Specific Delivery in Alzheimer's Disease.","authors":"Vanktesh Kumar, Violina Kakoty, Pankaj Wadhwa","doi":"10.1007/s12035-026-05901-0","DOIUrl":"https://doi.org/10.1007/s12035-026-05901-0","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive and the most common neurodegenerative condition, having a deleterious effect on memory, eventually leading to death. In the recent past, gene therapy has emerged as a promising and revolutionary treatment for AD. This study demonstrated that nucleic acid-loaded nanoparticles which deliver small interfering RNA through lipid nanoparticles successfully reduced Alzheimer's disease-related symptoms in preclinical models by decreasing amyloid-β levels and enhancing cognitive abilities. However, every rose has its thorn, as the output of gene therapy is considerably hampered by the physiological barriers of the brain, which include the blood-brain barrier and the brain's extracellular matrix (ECM). For this reason, many researchers have modified the gene delivery technique by developing 'brain penetrating' NPs coated with components that can prevent sticking to the ECM. Moreover, to overcome the challenge of low transgene expression and reduced accumulation in the brain, even when delivered at high doses, scientists have proposed that injection/delivery of gene vectors directly into a specific area in the brain can achieve maximum therapeutic efficacy. Hence, this review focuses on the advancements and advantages of region-specific delivery of nucleic acid-loaded NPs for the effective therapeutic management of AD.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840036","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-Specific Reversal of Stress-Induced Depressogenic Behaviors by Inhibition of HMGB1, TLR4, and NF-κB Signaling.","authors":"Aslıhan Bahadır-Varol, Bengisu Solgun, Gülce Küreli, Emre Cem Esen, Emine Eren-Koçak","doi":"10.1007/s12035-026-05908-7","DOIUrl":"https://doi.org/10.1007/s12035-026-05908-7","url":null,"abstract":"<p><p>Acute stress and inflammatory mediators are linked to stress-related mental disorders, yet sex-specific differences in the molecular pathways connecting them remain poorly understood. Male and female C57BL/6 mice underwent predator stress while restrained. Apathy/anhedonia and behavioral despair were assessed using the splash test (ST) and tail suspension test (TST). Neuroinflammatory signaling was assessed by immunohistochemistry through measurements of HMGB1 release and NF-κB nuclear translocation in the anterior cingulate cortex (ACC) and the nucleus accumbens (NAc). To further assess the roles of HMGB1, NF-κB and TLR4 in acute stress-induced behavioral changes in both sexes, mice were administered the respective inhibitors prior to stress, and changes in depression-like behaviors were subsequently assessed. Finally, microglial numbers and cleaved caspase-1 levels were evaluated by immunohistochemistry, and microglial ramifications were assessed by Sholl analysis. Acute stress induced increased immobility in the TST and decreased grooming in the ST in both sexes. Although stress triggered comparable increases in HMGB1 release and NF-κB translocation in both sexes, pharmacological inhibition of HMGB1, TLR4, and NF-κB exerted antidepressant effects exclusively in males. In females, none of the inhibitors was effective in reversing acute stress-induced immobility in TST and decreased grooming in ST. Although the numbers of microglia recruited by acute stress were similar in both sexes, they were more ramified in females regardless of stress exposure. Cleaved caspase-1 levels were elevated only in males after stress exposure, without any alteration in females. These findings underscore sex-specific differences in acute stress-induced alterations in the brain. The results suggest that downstream signaling pathways may differ by sex or that females possess protective mechanisms that constrain the behavioral consequences of neuroinflammation. This study highlights the necessity of considering sex as a critical biological variable in developing interventions for stress-related disorders.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dexmedetomidine Exerts Multi-level Effects to Ameliorate Alzheimer's Disease Pathology in the Adult Zebrafish Brain.","authors":"Dilek Nazli, Yusuf Kaan Poyraz, Kubilay Can, Dogac Ipekgil, Nilay Cakmak, Ebru Turhanlar-Sahin, Sevcan Hacoglu, Hale Aksu Erdost, Leyla Iyilikci, Gunes Ozhan","doi":"10.1007/s12035-026-05906-9","DOIUrl":"https://doi.org/10.1007/s12035-026-05906-9","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a complex neurodegenerative condition involving β-amyloid (Aβ) deposition, tau abnormalities, neuroinflammation, neuronal degeneration, and progressive impairment of cognitive functions. Despite extensive research, effective disease-modifying therapies remain limited, highlighting the need for translationally relevant models and repurposable therapeutic candidates. Dexmedetomidine (DEX), an α2-adrenergic receptor agonist with known neuroprotective properties, was investigated in an adult zebrafish model of AD established through cerebroventricular administration of Aβ42. DEX treatment significantly reduced Aβ accumulation and was associated with reduced amyloidogenic gene expression, indicating transcriptional changes in amyloidogenic pathway-related genes. DEX attenuated neuroinflammation by reducing glial activation, lowering pro-inflammatory cytokine gene expression, and increasing expression of the anti-inflammatory gene il10. Immunofluorescence assessment further demonstrated reduced astrogliosis and preserved neuronal marker integrity, as indicated by increased HuC/D levels. Interestingly, DEX attenuated Aβ-induced proliferative responses, characterized by decreased PCNA expression, while enhancing cleaved caspase-3 levels, suggesting changes in proliferation and apoptotic signaling under Aβ stress conditions. Behavioral assessments further demonstrated that DEX alleviated Aβ42-induced anxiety- and aggression-like behaviors, improving behavioral phenotypes in this model. Overall, these findings underscore the multi-level effects of DEX in modulating AD-related pathological features. As a clinically available agent, DEX represents a promising candidate for repurposing in neurodegenerative disease contexts. Further preclinical studies in mammalian models are warranted to validate its translational relevance and therapeutic potential.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139303/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MiR-144 Regulates Cognitive Dysfunction via NLRP3 Inflammasome and FoxO1/AdipoR Pathway in T2DM Mice.","authors":"Jinying Zhao, Yuliang Zhou, Shi Cheng, Jia Shen, Yahong Li, Zhipeng Xu","doi":"10.1007/s12035-026-05897-7","DOIUrl":"https://doi.org/10.1007/s12035-026-05897-7","url":null,"abstract":"<p><p>Type 2 diabetes mellitus (T2DM) is closely related to cognitive impairment, with underlying pathological mechanisms including chronic inflammation, synaptic dysfunction, and microglial dysregulation. Although microRNA-144 (miR-144) has been implicated in these processes, its precise role and molecular mechanisms remain unclear. T2DM mouse models were established using a high-fat diet combined with low-dose streptozotocin, and microglia-specific miR-144 intervention was achieved in the hippocampus via bilateral injection of adeno-associated virus. Cognitive function was assessed using the novel object recognition and Morris water maze tests, while synaptic plasticity, microglial phenotype, neuroinflammation, and Tau pathology were evaluated by immunofluorescence, Western blot, Golgi staining, transmission electron microscopy, and electrophysiology. Our results showed that overexpression of miR-144 mimicked the pathological state of T2DM, leading to impaired learning and memory, neuronal dysfunction, reduced expression of synaptic proteins, and decreased dendritic spine density. Additionally, miR-144 overexpression significantly suppressed FoxO1 and AdipoR1/AdipoR2 expression while inducing microglial M1 polarization, activating downstream NLRP3-mediated neuroinflammatory responses, and increasing Tau phosphorylation. Conversely, miR-144 knockdown effectively ameliorated these pathological changes and provided neuroprotection. These findings suggest that miR-144 could serve as a promising biomarker and therapeutic target for T2DM-related cognitive impairment. This study offers novel insights into the underlying mechanisms of T2DM-related cognitive impairment and provides an experimental foundation for exploring miR-144-based intervention strategies.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840071","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":"From Cerebrospinal Fluid to Blood Draw: Plasma p-Tau217 as a Non-Invasive Biomarker for Alzheimer's Disease: A Fagan Nomogram-Based Meta-Analytic Study.","authors":"Nesma M Gebril, Abdelrahman M Elettreby, Abeer H Younis, Mostafa Hossam El Din Moawad, Afaf M Hafez, Gamal El Sayed, Kariman M Abdelrahman, Sarah M El-Kot","doi":"10.1007/s12035-026-05864-2","DOIUrl":"10.1007/s12035-026-05864-2","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the leading cause of dementia worldwide and is pathologically defined by amyloid-β and tau accumulation. Current diagnostic methods, such as PET imaging and cerebrospinal fluid (CSF) assays, are accurate but invasive, costly, and limited in accessibility. Plasma phosphorylated tau at threonine 217 (p-tau217) has emerged as a promising blood-based biomarker, but evidence from individual studies remains heterogeneous. We conducted a systematic review and meta-analysis to evaluate the diagnostic performance of plasma p-tau217 for AD. Following PRISMA guidelines, PubMed, Scopus, and Web of Science were searched up to July 2025. Eligible studies included clinical or biomarker-defined AD cohorts that reported plasma p-tau217 accuracy against amyloid or tau positivity or clinical diagnosis. Data on sensitivity, specificity, likelihood ratios, and diagnostic odds ratio (DOR) were extracted. Study quality was assessed using QUADAS-2. Pooled estimates were calculated using a Bayesian bivariate model, and heterogeneity was explored with meta-regression and subgroup analyses. Twenty-seven studies including 19,652 participants were analyzed. Plasma p-tau217 demonstrated high diagnostic accuracy for biomarker-defined AD, with pooled sensitivity of 85.4% (95% posterior intervals [PI]: 81.4-88.7), specificity of 88.0% (95% PI: 85.1-90.6), positive likelihood ratio (PLR) 7.13, negative likelihood ratio (NLR) 0.167, and DOR 42.7. Performance was consistent across amyloid PET and CSF reference standards. Subgroup analyses showed robust accuracy for amyloid positivity (sensitivity 87.3%, specificity 85.5%), tau positivity (sensitivity 84.9%, specificity 93.8%), and clinical AD diagnosis (sensitivity 72.9%, specificity 89.5%). Plasma p-tau217 consistently outperformed other blood biomarkers and correlated with cognitive decline, frailty, and behavioral impairment. Risk of bias was generally low, with no major publication bias detected. This meta-analysis indicates that plasma p-tau217 demonstrates promising diagnostic accuracy for detecting AD pathology across biomarker-defined reference standards. However, heterogeneity across assays, populations, and reference definitions, along with the use of optimized cut-offs in some studies and the limited power of publication-bias assessments, warrant cautious interpretation. Plasma p-tau217 appears well suited as a triage biomarker to guide confirmatory testing, but further large, prospectively designed studies with standardized assays and externally validated thresholds are needed before widespread clinical implementation.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Mechanisms of Retinal Damage in NMOSD via Müller Glial Cell Stimulation with Patient Sera.","authors":"Sahra Kabiri, İrfan Burak Göloğlu, Ahmetcan Sezen, Ceren Tuncer, Mohammad Haroon Qureshi, Rabia Gökçen Gözübatik Çelik, Afsun Şahin, Ayşe Altıntaş","doi":"10.1007/s12035-026-05892-y","DOIUrl":"10.1007/s12035-026-05892-y","url":null,"abstract":"<p><p>Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune CNS disease that frequently causes severe optic neuritis, yet the molecular mechanisms driving retinal damage remain incompletely understood, especially across different NMOSD subgroups. Müller glial cells, which maintain retinal water-ion homeostasis through AQP4 and Kir4.1 channels, may represent a primary retinal target of circulating NMOSD-related autoantibodies and serum factors. We investigated how sera from AQP4-IgG+, MOG-IgG+, and double-seronegative (DSN) NMOSD patients affect the expression and localization of key Müller cell biomarkers. Human MIO-M1 Müller cells were stimulated with complement-inactivated patient or healthy control sera, and protein/mRNA levels of AQP4, Kir4.1, CRALBP, VEGF, and IL-6 were evaluated using immunofluorescence, Western blotting, and RT-qPCR. AQP4 membrane localization and internalization were assessed using WGA and EEA1 colocalization analyses. AQP4-IgG+ sera uniquely induced a marked reduction in AQP4 and Kir4.1 protein expression, together with mild AQP4 internalization and reduced membrane association. Despite protein loss, AQP4 and Kir4.1 transcripts were significantly upregulated, indicating a compensatory transcriptional response to antibody-mediated depletion. MOG-IgG + sera produced no major changes in the examined markers. In contrast, DSN sera selectively increased VEGF expression at both protein and mRNA levels, suggesting an alternative, antibody-independent mechanism of Müller cell activation. IL-6 expression showed non-significant changes across groups. These findings demonstrate subgroup-specific retinal glial responses to patient sera, with AQP4-IgG mediating early complement-independent loss of the AQP4-Kir4.1 water-ion channel complex, and DSN sera engaging distinct VEGF-related pathways. Our study establishes Müller cells as active contributors to NMOSD-associated retinal pathology and provides a foundation for exploring subgroup-tailored changes.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}