Experimental Neurology最新文献

{"title":"The role of LINGO-1 in regulating CB1R/TrkB signalling and GABAergic interneurons in Alzheimer's disease pathogenesis.","authors":"Qi He, Lin Jiang, Feng-Lei Chao, Chun-Ni Zhou, Lei Zhang, Yu-Ning Zhou, Yi-Ying Wang, Yu-Hui Deng, Jing Tang, Yanmin Luo, Xin Liang, Jing Li, Yi Zhang, Yong Tang","doi":"10.1016/j.expneurol.2025.115319","DOIUrl":"https://doi.org/10.1016/j.expneurol.2025.115319","url":null,"abstract":"<p><p>Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1) is a neuronal system-specific transmembrane protein that is highly expressed in the brains of patients with Alzheimer's disease (AD), and our previous findings showed that LINGO-1 antagonism can improve cognitive function and protect hippocampal GABAergic neurons in AD model mice. However, the specific mechanism underlying these effects is not clear. In this study, an adeno-associated virus (AAV) was used to directly interfere with hippocampal LINGO-1 in vivo, and LINGO-1 antagonists, cannabinoid type 1 receptor (CB1R) agonists, and CB1R antagonists were used to treat mouse hippocampal neurons (HT22 neurons) in vitro. We found that overexpressing hippocampal LINGO-1 in normal young mice impaired spatial learning and memory and reduced hippocampal CB1R protein levels, whereas silencing hippocampal LINGO-1 in AD model mice had the opposite effect. Additionally, antagonizing LINGO-1 increased CB1R/tyrosine kinase receptor B (TrkB) signalling and rescued CB1R- rich cholecystokinin-GABAergic (CCK-GABAergic) interneurons in HT22 neurons transduced with an APP/PS1-expressing virus. Competitive inhibition of LINGO-1 and CB1R was observed, and antagonizing LINGO-1 reversed the changes in HT22 neurons caused by the inhibition of CB1R, such as the decreases in the protein levels of doublecortin (DCX), TrkB, and phosphorylated TrkB (p-TrkB). These findings provide an important scientific basis for further exploration of the mechanism by which LINGO-1 regulates cognitive function and hippocampal GABAergic neurons in AD model mice.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115319"},"PeriodicalIF":4.6,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180681","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":"The role of astrocyte-derived extracellular vesicles in cellular microenvironment remodeling after spinal cord injury: A study based on quantitative proteomics analysis","authors":"Zhenghuan Zhu ,&nbsp;Yi Xu ,&nbsp;Kejie Wang ,&nbsp;Xu Xu ,&nbsp;Yu Song ,&nbsp;Baizhen Zhao ,&nbsp;Wenge Ding ,&nbsp;Jinbo Liu ,&nbsp;Zhiwen Song","doi":"10.1016/j.expneurol.2025.115321","DOIUrl":"10.1016/j.expneurol.2025.115321","url":null,"abstract":"<div><div>After spinal cord injury (SCI), astrocytes (AS), the most abundant glial cells in the central nervous system, closely interact with other nerve cells. The precise mechanism by which astrocytes remodel the cellular microenvironment (CME) remains unclear; however, the extracellular vesicles (EVs) they release may facilitate communication between cells by transporting biological macromolecules. This study aimed to elucidate the role of astrocyte-derived EVs in modulating CME after SCI. An <em>in vitro</em> model of reactive astrocytes (RA) was developed under simulated SCI conditions, followed by proteomic analysis of EVs isolated from RA and AS. Differential protein expression was assessed using quantitative proteomics, complemented by gene set enrichment analysis to elucidate the associated biological functions. Our results indicate that AS-EVs provide neuroprotective benefits by attenuating microglial activation, decreasing neuronal apoptosis, promoting axonal growth, and facilitating the maturation of oligodendrocyte precursor cells, thereby improving motor function recovery in murine models. Conversely, RA-EVs exhibited deleterious effects, exacerbating inflammation and impeding functional recovery. C<img>C Motif Chemokine Ligand 7 (CCL7) was identified as a critical secretory protein mediating these adverse effects. These findings elucidate the neuroprotective and regenerative mechanisms mediated by astrocyte-derived EVs, highlighting the therapeutic potential of CCL7-targeted interventions in promoting recovery after SCI.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115321"},"PeriodicalIF":4.6,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144167583","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":"Osteocalcin modulates Abeta42 aggregation to aid in amyloid reduction in mouse models of Alzheimer's disease.","authors":"Viji Vijayan, Ibrar Ahmad Siddique, Sakshi Gupta, Evanka Madan Chopra, Navya Raj, Avadhesha Surolia, Sarika Gupta","doi":"10.1016/j.expneurol.2025.115322","DOIUrl":"https://doi.org/10.1016/j.expneurol.2025.115322","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by overexpression of amyloid-beta in the brain, particularly the toxic Abeta-42 form. Recent studies have identified osteocalcin, a peptide traditionally associated with bone, to modulate cognitive function in the AD brain. Osteocalcin exists in two forms: the undercarboxylated (uOC) and carboxylated (cOC) forms. This study investigates the role of uOC in modulating Abeta42 aggregation and its potential therapeutic implications for AD. Administration of uOC, but not cOC, improved both spatial learning and exploratory behavior of 5xFAD transgenic Alzheimer mice. Further investigation showed that uOC reduced the level of insoluble Abeta42 in the brain and increased the level of soluble Abeta42. There was increase in mRNA levels of CD36 in uOC treated 5xFAD transgenic brain alongside upregulation of neuroprotectants like Adipoq and Ahsg (fetuin). We explored the mechanisms underlying the influence of uOC on Aβ42 dynamics and understood that uOC interacts with Glu residues to form non-toxic early tube-like intermediates (A-O) before advancing to late mature Abeta42 fibrils. These intermediates enable Abeta42 uptake by glial cells by upregulating the cell surface expression of CD36 and reducing TNF-alpha production. Collectively, the study sheds light on the fact that uOC modulates Abeta42 dynamics and this interaction is warranted for Abeta42 uptake and clearance. The study provides a novel dimension for the treatment of amyloid disorders like AD.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115322"},"PeriodicalIF":4.6,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180852","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":"Intracerebroventricular phospho-tau immunotherapy alleviates cortical phospho-tau burden and motor phenotype in a neuron-specific P301S tauopathy mouse","authors":"S. Kemppainen ,&nbsp;M. Aramburu-Núñez ,&nbsp;H. Koivisto ,&nbsp;A. Posado-Fernández ,&nbsp;M.R. Felix-Garcia ,&nbsp;K. Nurminen ,&nbsp;S. Häkli ,&nbsp;E. Abelli-Deulofeu ,&nbsp;M. Kaisto ,&nbsp;A. Custodia ,&nbsp;L. van Olst ,&nbsp;R.-M. Willman ,&nbsp;P. Mäkinen ,&nbsp;P.O. Miettinen ,&nbsp;M. Schouten ,&nbsp;Ramón Iglesias-Rey ,&nbsp;A. Kamermans ,&nbsp;H. Martiskainen ,&nbsp;T. Rauramaa ,&nbsp;H.E. de Vries ,&nbsp;H. Tanila","doi":"10.1016/j.expneurol.2025.115315","DOIUrl":"10.1016/j.expneurol.2025.115315","url":null,"abstract":"<div><div>Pathological tau accumulation disrupts neuronal function, leading to neurodegeneration and dementia in tauopathies, such as Alzheimer's disease and frontotemporal dementia. Despite the progression of several anti-tau therapies to clinical trials, no disease-modifying treatments for tauopathies exist. Tau hyperphosphorylation is a key factor in pathology progression. Among all tau phosphorylation sites targeted in preclinical passive immunization studies, the classic AT8 pathological tau phosphorylation sites have remained understudied. Thus, we investigated the potential of immunotherapy against phosphorylated tau (pTau) in a P301S mouse model of tauopathy. We administered a new monoclonal B6 antibody that targets tau phosphorylation sites at serine 202, threonine 205 and serine 208 either systemically for 3 months or locally into the cerebral ventricles for 1 or 2 months via an osmotic minipump. Systemic administration failed to reach the brain effectively, and subsequently, was not able to alleviate the progressive motor impairment seen in this tauopathy mouse model. By contrast, intraventricular administration improved motor function in earlier stages of pathology but had a lesser effect in later stages. The local administration for 8 weeks reduced the number of pTau positive neurons in cortex and hippocampus. Our findings indicate that targeting the classical pathological tau phosphorylation sites can ameliorate tau pathology and improve function in a mouse tauopathy model. These results add to growing evidence supporting the efforts in developing tau-targeting immunotherapies for neurodegenerative diseases associated with pathological tau deposits.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115315"},"PeriodicalIF":4.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126927","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":"Lactate exacerbates neuroinflammation in sepsis-associated encephalopathy via promoting neutrophil migration from skull bone marrow to the meninge","authors":"Yutao Du ,&nbsp;Yicheng Li ,&nbsp;Fanfan Ye ,&nbsp;Hanxiao Cai ,&nbsp;Wenmian Huang ,&nbsp;Tao Liu ,&nbsp;Xiaochang Xue ,&nbsp;Guodong Feng","doi":"10.1016/j.expneurol.2025.115318","DOIUrl":"10.1016/j.expneurol.2025.115318","url":null,"abstract":"<div><div>Sepsis-associated encephalopathy (SAE) is one of the most common and severe complications of sepsis. Although lactate and neutrophils play pivotal roles in SAE, the mechanisms linking lactate, neutrophils, and neuroinflammation in SAE remain largely unclear.</div><div>In this study, SAE model was induced in C57BL/6 J mice via intraperitoneal lipopolysaccharide (LPS) injection, with lactate production inhibited by administering the lactate dehydrogenase inhibitor FX-11. Neutrophils were visualized by immunofluorescence, and immune cell subsets were quantified via flow cytometry. Our findings revealed that lactate levels in the skull bone marrow (SBM) were significantly elevated in SAE mice, accompanied by decreased SBM neutrophils and increased neutrophil extravasation into the meninges. These effects were reproduced in exogenous lactate-administered normal mice. Further studies identified that a CD31⁺ channel between the SBM and meninges facilitates neutrophil mobilization and migration. Notably, FX-11 injection significantly alleviated SAE in mice, as indicated by reduced SBM lactate production, inhibited neutrophil mobilization, decreased meningeal neutrophil extravasation, suppressed microglial activation and reduced hippocampal inflammatory cytokines as well.</div><div>In summary, our results show that elevated lactate levels in the SBM promote neutrophil migration between the skull and meninges and hence exacerbate SAE neuroinflammation, which can be potently improved in the presence of the lactate inhibitor FX-11. The migration of neutrophils influenced by lactate in the skull–meninges–brain axis could be a potential therapeutic target for the treatment of SAE.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115318"},"PeriodicalIF":4.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132330","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":"Salvianolic acid B exerts cerebroprotective effects after traumatic brain injury via Nrf2-dependent antioxidant and anti-inflammatory cascades","authors":"Dacheng Wang ,&nbsp;Yanxia Geng ,&nbsp;Fengming Gu ,&nbsp;Yan Zhuang ,&nbsp;Hai Lv ,&nbsp;Xue He ,&nbsp;Haicheng Yang ,&nbsp;Jun Lu","doi":"10.1016/j.expneurol.2025.115305","DOIUrl":"10.1016/j.expneurol.2025.115305","url":null,"abstract":"<div><h3>Background</h3><div>Oxidative stress and inflammatory responses play crucial roles in the development of secondary brain injury following traumatic brain injury (TBI). Thus, this study aimed to investigate the potential cerebroprotective effects of salvianolic acid B (SalB) in mitigating oxidative stress and inflammatory responses post-TBI through the activation of Nrf2.</div></div><div><h3>Purpose</h3><div>This study aims to investigate the potential cerebroprotective effects of SalB in ameliorating oxidative stress and inflammatory responses following TBI by activating Nrf2, thereby laying a foundation for TBI treatment.</div></div><div><h3>Study design</h3><div>Controlled cortical impact and hydrogen peroxide were employed to replicate TBI in animal and cellular models, respectively.Behavioral studies predict neural function, Western Blot (WB) predicts oxidative stress, immunofluorescence and ELISA predict inflammatory response.The Nrf2 inhibitor ML385 was employed to investigate the involvement of the Nrf2 pathway in mediating the protective effects of SalB.</div></div><div><h3>Methods</h3><div>SalB was delivered via intraperitoneal injection 1 h after TBI induction, with its neuroprotective efficacy evaluated across a range of concentrations. In the cellular assay, SalB was used to incubate cells simultaneously with H₂O₂. WB analysis was employed to quantify protein levels, while malondialdehyde, glutathione, superoxide intensity, and reactive oxygen radical probes were utilized to evaluate oxidative stress. Immunofluorescence and ELISA techniques were used to characterize microglia phenotype and inflammatory response. Behavioral assays were also conducted to evaluate neurological function. The Nrf2 inhibitor ML385 was employed to investigate the involvement of the Nrf2 pathway in mediating the protective effects of SalB.</div></div><div><h3>Results</h3><div>Animal and cellular experiments indicate that SalB can mitigate oxidative stress through the Nrf2/Peroxiredoxin 2 pathway, and reduce inflammatory response via the Nrf2/Toll-like receptor 4/Myeloid differentiation primary response protein 88 pathway in a dose-dependent manner. Consequently, SalB demonstrates efficacy in enhancing neurological function following TBI. Conversely, the inhibitory effects of ML385 counteract the antioxidant and anti-inflammatory properties of SalB.</div></div><div><h3>Conclusions</h3><div>SalB exerts its beneficial effects post-TBI through Nrf2-dependent antioxidants and as anti-inflammatory responses.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115305"},"PeriodicalIF":4.6,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093231","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":"Deciphering the NLRP3 inflammasome in diabetic encephalopathy: Molecular insights and emerging therapeutic targets","authors":"Xinyi Zeng ,&nbsp;Yi Yuan ,&nbsp;Yujia Li ,&nbsp;Ziyan Hu ,&nbsp;Shan Hu","doi":"10.1016/j.expneurol.2025.115304","DOIUrl":"10.1016/j.expneurol.2025.115304","url":null,"abstract":"<div><div>Diabetic encephalopathy (DE) is a neurological complication characterized by neuroinflammation, cognitive impairment, and memory decline, with its pathogenesis closely linked to the activation of the NLRP3 inflammasome. As a central regulator of the innate immune system, the NLRP3 inflammasome plays a pivotal role in DE progression by mediating neuroinflammation, pyroptosis, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum (ER) stress, and microglial polarization. This review systematically explores the molecular mechanisms by which the NLRP3 inflammasome contributes to DE, focusing on its role in neuroinflammatory cascades and neuronal damage, as well as the diabetes-associated physiological changes that exacerbate DE pathogenesis. Furthermore, we summarize emerging therapeutic strategies targeting the NLRP3 inflammasome, including small-molecule inhibitors and bioactive compounds derived from traditional herbal medicine, highlighting their potential for DE treatment. These findings not only advance our understanding of DE but also provide a foundation for developing NLRP3-targeted pharmacological interventions.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115304"},"PeriodicalIF":4.6,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144083932","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":"Anti-Nogo-A antibody treatment six months post-stroke results in neuroplasticity and improved functional outcome","authors":"Shih-Yen Tsai ,&nbsp;Son T. Ton ,&nbsp;Timothy E. O'Brien ,&nbsp;Douglas G. Wallace ,&nbsp;Russ P. Nockels ,&nbsp;Gwendolyn L. Kartje","doi":"10.1016/j.expneurol.2025.115306","DOIUrl":"10.1016/j.expneurol.2025.115306","url":null,"abstract":"<div><div>We have reported that anti-Nogo-A antibody therapy is effective in enhancing neuroplasticity and improving functional recovery when given up to two months post-stroke. Here we assessed whether this therapy would be effective at a much later time point post-stroke. Rats underwent middle cerebral artery occlusion to permanently impair their preferred forelimb and six months later were given either anti-Nogo-A antibody, control antibody or no antibody. Rats receiving anti-Nogo-A antibody showed significant behavioral improvement that correlated with cortico-rubral plasticity, indicating that anti-Nogo-A antibody is effective even long after the injury has occurred, opening the treatment window for many stroke survivors.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115306"},"PeriodicalIF":4.6,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093225","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":"Remote ischemic conditioning–induced shift from a vulnerable to a tolerant penumbra: A proteomic perspective","authors":"Petra Bonová ,&nbsp;Jana Končeková ,&nbsp;Miroslava Némethová ,&nbsp;Marko Morávek ,&nbsp;Peter Baráth ,&nbsp;Maksym Danchenko ,&nbsp;Martin Bona","doi":"10.1016/j.expneurol.2025.115307","DOIUrl":"10.1016/j.expneurol.2025.115307","url":null,"abstract":"<div><div>The concept of the ischaemic penumbra – stroke tissue with the potential to survive – has opened the door to a wide range of experimental strategies that could benefit the recovery of patients after a stroke. In this study, we used proteomic analysis to examine how remote ischaemic postconditioning (RIPC) mediates a shift from a vulnerable to a tolerant penumbra. We identified 450 differentially abundant proteins between the control group and the groups subjected to ischaemia via middle cerebral artery occlusion with or without RIPC during infarct expansion. The majority of proteins were downregulated following RIPC. Based on Gene Ontology enrichment analysis, we uncovered 24 gene sets significantly influenced during the reprogramming from a vulnerable to a tolerant penumbra. RIPC treatment positively impacted the synthesis of proteins enriched in the cytosol (GO:0005829) but inhibited the abundance of proteins belonging to the cytoskeleton (GO:0005874 microtubule) and the glutamatergic synapse (GO:0098978). The shift to a tolerant phenotype involved overexpression of aminopeptidases (GO:0004177) related to proteolysis (GO:0006508). RIPC also downregulated proteins involved in the tricarboxylic acid cycle (GO:0006099), adenosine triphosphate (ATP) binding (GO:0005524), and ATP hydrolysis (GO:0016887). We validated our proteomic findings by selecting two candidate genes (Map2 and Tubb3) for immunofluorescence. We identified the low-molecular-weight Map2 isoform as a potential marker of the shift from a vulnerable to a tolerant penumbra. In summary, our findings have revealed novel avenues for multimodal investigation of reprogramming the penumbra as part of recovery from stroke.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115307"},"PeriodicalIF":4.6,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093228","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":"The overexpression of miR-146a in hippocampal microglia via IRAK1/TRAF6/NF-κB pathway improves cognitive function in diabetic mice","authors":"Jingyu Zhang ,&nbsp;Xiaoyun Lin ,&nbsp;Qing Huang ,&nbsp;Zhang Fu ,&nbsp;Yihuan Huang ,&nbsp;Zhiqing Chen ,&nbsp;Ningning Li ,&nbsp;Xiahong Lin","doi":"10.1016/j.expneurol.2025.115291","DOIUrl":"10.1016/j.expneurol.2025.115291","url":null,"abstract":"<div><h3>Background and objective</h3><div>Diabetic encephalopathy (DEP), a central nervous system complication of diabetes, is primarily characterized by cognitive dysfunction. Despite its high prevalence and significant risks, the pathogenesis remains poorly understood. This study investigates the effects and mechanisms of miR-146a on cognitive function in DEP mice.</div></div><div><h3>Methods</h3><div>Type 2 diabetic mice models were established by feeding a high-fat diet and administering a low-dose of streptozotocin. And the Morris water maze test was conducted to assess the learning and memory. The adeno-associated virus was delivered into hippocampus by stereotactic injection to overexpress miR-146a in microglia. The mRNA and protein expression levels were determined by quantitative real-time polymerase chain reaction, immunofluorescence, Western blot, and enzyme-linked immunosorbent assay.</div></div><div><h3>Results</h3><div>DEP mice exhibited significantly reduced miR-146a expression in hippocampal microglia. This reduction was associated with elevated IRAK1, TRAF6, and NF-κB expression, increased markers of pro-inflammatory microglial phenotypes (CD86 and iNOS), and decreased markers of anti-inflammatory phenotypes (Arg-1 and CD206). Pro-inflammatory cytokines TNF-α and IL-6 were elevated, while anti-inflammatory IL-10 was reduced. Eventually, neuronal apoptosis and cognitive dysfunction were evident. Overexpression of miR-146a in hippocampal microglia reversed these molecular and phenotypic abnormalities, decreased neuronal apoptosis, and significantly improved cognitive performance in diabetic mice.</div></div><div><h3>Conclusion</h3><div>Downregulation of miR-146a in hippocampal microglia disrupts immune homeostasis through the IRAK1/TRAF6/NF-κB pathway, contributing to DEP. Targeted overexpression of miR-146a restores immune homeostasis, reduces neuronal apoptosis, and ameliorates cognitive impairment.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115291"},"PeriodicalIF":4.6,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993221","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}