Neurobiology of Disease最新文献

{"title":"Alzheimer's disease risk ABCA7 p.A696S variant disturbs the microglial response to amyloid pathology in mice","authors":"Xiaoye Ma ,&nbsp;Dmitry Prokopenko ,&nbsp;Ni Wang ,&nbsp;Tomonori Aikawa ,&nbsp;Younjung Choi ,&nbsp;Can Zhang ,&nbsp;Dan Lei ,&nbsp;Yingxue Ren ,&nbsp;Keiji Kawatani ,&nbsp;Skylar C. Starling ,&nbsp;Ralph B. Perkerson ,&nbsp;Bhaskar Roy ,&nbsp;Astrid C. Quintero ,&nbsp;Tammee M. Parsons ,&nbsp;Yining Pan ,&nbsp;Zonghua Li ,&nbsp;Minghui Wang ,&nbsp;Hanmei Bao ,&nbsp;Xianlin Han ,&nbsp;Guojun Bu ,&nbsp;Takahisa Kanekiyo","doi":"10.1016/j.nbd.2025.106813","DOIUrl":"10.1016/j.nbd.2025.106813","url":null,"abstract":"<div><div>The adenosine triphosphate–binding cassette transporter A7 (<em>ABCA7</em>) gene is ranked as one of the top susceptibility loci for Alzheimer's disease (AD). While ABCA7 mediates lipid transport across cellular membranes, ABCA7 loss of function has been shown to exacerbate amyloid-β (Aβ) pathology and compromise microglial function. Our family-based study uncovered an extremely rare <em>ABCA7</em> p.A696S variant that was substantially segregated with the development of AD in 3 African American families. Using the knockin mouse model, we investigated the effects of ABCA7-A696S substitution on amyloid pathology and brain immune response in 5xFAD transgenic mice. Importantly, our study demonstrated that ABCA7-A696S substitution reduces amyloid plaque–associated microgliosis and increases dystrophic neurites around amyloid deposits compared to control mice. We also found increased X-34–positive amyloid plaque burden in 5xFAD mice with ABCA7-A696S substitution, while there was no evident difference in insoluble Aβ levels between mouse groups. Thus, ABCA7-A696S substitution may disrupt amyloid compaction resulting in aggravated neuritic dystrophy due to insufficient microglia barrier function. In addition, we observed that ABCA7-A696S substitution disturbs the induction of proinflammatory cytokines interleukin 1β and interferon γ in the brains of 5xFAD mice, although some disease-associated microglia gene expression, including <em>Trem2</em> and <em>Tyrobp,</em> are upregulated. Lipidomics also detected higher total lysophosphatidylethanolamine levels in the brains of 5xFAD mice with ABCA7-A696S substitution than controls. These results suggest that ABCA7-A696S substitution might compromise the adequate innate immune response to amyloid pathology in AD by modulating brain lipid metabolism, providing novel insight into the pathogenic mechanisms mediated by ABCA7.</div></div><div><h3>One sentence summary</h3><div>A rare Alzheimer's disease risk <em>ABCA7</em> p.A696S variant compromises microglial response to amyloid pathology.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106813"},"PeriodicalIF":5.1,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066579","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":"Mutations in hnRNP A1 drive neurodegeneration and alternative RNA splicing of neuronal gene targets","authors":"Ansalna Ansari ,&nbsp;Patricia A. Thibault ,&nbsp;Hannah E. Salapa ,&nbsp;Joseph-Patrick W.E. Clarke ,&nbsp;Michael C. Levin","doi":"10.1016/j.nbd.2025.106814","DOIUrl":"10.1016/j.nbd.2025.106814","url":null,"abstract":"<div><div>RNA binding protein dysfunction is a pathogenic feature of multiple neurological diseases, including multiple sclerosis (MS). Neurodegeneration (the loss of, or damage to neurons and axons) is the primary driver of disease progression in MS. Herein, we utilized a novel, neuron-specific model of neurodegeneration by transducing primary mouse neurons with mutant forms of the RNA binding protein heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) identified from MS patients, including one within the M9-nuclear localization sequence of hnRNP A1 (A1(P275S)) and a second in the prion-like domain of hnRNP A1 (A1(F263S)) to test the hypothesis that neuronal hnRNP A1 dysfunction drives neurodegeneration in MS.</div><div>Examination of hnRNP A1 localization in neurons revealed an increase in nucleocytoplasmic mislocalization in neurons transduced with A1(P275S), but not A1(F263S). Yet, both A1(F263S) and A1(P275S) induced neurodegeneration evidenced by significant reductions in total neurite length and complexity and an increase in FluoroJade-C neuronal cell body staining. RNA sequencing and differential alternative splicing analysis of mutant-expressing neurons revealed dramatic changes in alternative RNA splicing of transcripts critical to neuronal function. Further, amyloid precursor protein (<em>APP</em>), a marker for neurodegeneration in MS, showed differential splicing in mutant-expressing neurons, which was confirmed in MS brains with hnRNP A1 dysfunction.</div><div>Overall, we have identified that hnRNP A1 plays a complex role in neuronal function and regulation by mediating the alternative splicing of neuron-specific transcripts. When neuronal hnRNP A1 function is impaired, as in disease, resultant dysfunction propagates through multiple pathways that may influence the progression of neurodegeneration in MS.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106814"},"PeriodicalIF":5.1,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059385","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":"Unveiling the significance of AKAP79/150 in the nervous system disorders: An emerging opportunity for future therapies?","authors":"Chen-Chao Chu ,&nbsp;Ya-Hui Hu ,&nbsp;Gui-Zhou Li ,&nbsp;Jiang Chen ,&nbsp;Ning-Ning Zhang ,&nbsp;Yi-Xue Gu ,&nbsp;Shi-Yu Wu ,&nbsp;Hai-Feng Zhang ,&nbsp;Yang-Yang Xu ,&nbsp;Hong-Li Guo ,&nbsp;Xin Tian ,&nbsp;Feng Chen","doi":"10.1016/j.nbd.2025.106812","DOIUrl":"10.1016/j.nbd.2025.106812","url":null,"abstract":"<div><div>A-kinase anchoring protein 79/150 (AKAP79/150) is a crucial scaffolding protein that positions various proteins at specific synaptic sites to modulate excitatory synaptic intensity. As our understanding of AKAP79/150's biology deepens, along with its significant role in the pathophysiology of various human disorders, there is growing evidence that reveals new opportunities for therapeutic interventions. In this review, we examine the fundamental structure and primary functions of AKAP79/150, emphasizing its pathophysiological mechanisms in different nervous system disorders, particularly inflammatory pain, epilepsy, depression, and Alzheimer's disease. We also discuss its potential therapeutic implications for patients suffering from these conditions.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106812"},"PeriodicalIF":5.1,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047153","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":"Huntingtin plays an essential role in the adult hippocampus","authors":"Jessica C. Barron ,&nbsp;Laura J. Dawson ,&nbsp;Samantha J. Carew ,&nbsp;Mackenzie C. Grace ,&nbsp;Kelsie A. Senior ,&nbsp;Katelyn C. Ryan ,&nbsp;Firoozeh Nafar ,&nbsp;Craig S. Moore ,&nbsp;Jacqueline Blundell ,&nbsp;Matthew P. Parsons","doi":"10.1016/j.nbd.2025.106810","DOIUrl":"10.1016/j.nbd.2025.106810","url":null,"abstract":"<div><div>The consequences of non-pathogenic huntingtin (HTT) reduction in the mature brain are of substantial importance as clinical trials for numerous HTT-lowering therapies are underway; many of which are non-selective in that they reduce both mutant and wild type protein variants. In this study, we injected CaMKII-promoted AAV-Cre directly into the hippocampus of adult HTT floxed mice to explore the role of wild-type huntingtin (wtHTT) in adult hippocampal pyramidal neurons and the broader implications of its loss. Our findings reveal that wtHTT depletion results in profound macroscopic morphological abnormalities in hippocampal structure, accompanied by significant reactive gliosis. At the synaptic level, we identified a marked reduction in presynaptic terminals 1–2 months following wtHTT loss; this was contrasted by an increased density of postsynaptic mushroom spines and larger amplitudes of spontaneous excitatory postsynaptic currents, indicative of disrupted synaptic homeostasis. Furthermore, intrinsic neuronal excitability was significantly diminished in CA1 pyramidal neurons lacking wtHTT, and we observed a complete loss of NMDA receptor-dependent long-term potentiation. Unexpectedly, synapse density returned to control levels 6–8 months following wtHTT loss, despite the ongoing presence of macroscopic morphological abnormalities, altered anxiety-related behaviors and clear impairments in spatial learning and memory. Overall, these findings uncover a previously unrecognized role of wtHTT as a critical regulator of hippocampal function in the mature brain, and highlight the hippocampus as a potentially vulnerable region to the adverse effects of non-selective HTT reduction.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106810"},"PeriodicalIF":5.1,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040539","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":"Resting-state electroencephalographic rhythms depend on sex in patients with dementia due to Parkinson's and Lewy Body diseases: An exploratory study","authors":"Claudio Del Percio ,&nbsp;Roberta Lizio ,&nbsp;Susanna Lopez ,&nbsp;Giuseppe Noce ,&nbsp;Dharmendra Jakhar ,&nbsp;Matteo Carpi ,&nbsp;Burcu Bölükbaş ,&nbsp;Andrea Soricelli ,&nbsp;Marco Salvatore ,&nbsp;Bahar Güntekin ,&nbsp;Görsev Yener ,&nbsp;Federico Massa ,&nbsp;Dario Arnaldi ,&nbsp;Francesco Famà ,&nbsp;Matteo Pardini ,&nbsp;Raffaele Ferri ,&nbsp;Michele Salerni ,&nbsp;Bartolo Lanuzza ,&nbsp;Fabrizio Stocchi ,&nbsp;Laura Vacca ,&nbsp;Claudio Babiloni","doi":"10.1016/j.nbd.2025.106807","DOIUrl":"10.1016/j.nbd.2025.106807","url":null,"abstract":"<div><div>Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) are more prevalent in males than females. Furthermore, they typically showed abnormally high delta (&lt; 4 Hz) and low alpha (8–10 Hz) rhythms from resting-state electroencephalographic (rsEEG) activity. Here, we hypothesized that those abnormalities may depend on the patient's sex.</div><div>An international database provided clinical-demographic-rsEEG datasets for cognitively unimpaired older (Healthy; <em>N</em> = 49; 24 females), PDD (<em>N</em> = 39; 13 females), and DLB (<em>N</em> = 38; 15 females) participants. Each group was stratified into matched female and male subgroups. The rsEEG rhythms were investigated across the individual rsEEG delta, theta, and alpha frequency bands based on the individual alpha frequency peak. The eLORETA freeware was used to estimate cortical rsEEG sources.</div><div>In the Healthy group, widespread rsEEG alpha source activities were greater in the females than in the males. In the PDD group, widespread rsEEG delta source activities were lower and widespread rsEEG alpha source activities were greater in the females than in the males. In the DLB group, central-parietal rsEEG delta source activities were lower, and posterior rsEEG alpha source activities were greater in the females than in the males.</div><div>These results suggest sex-dependent hormonal modulation of neuroprotective-compensatory neurophysiological mechanisms in PDD and DLB patients underlying the generation of rsEEG delta and alpha rhythms, which should be considered in the treatment of vigilance dysregulation in those patients.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106807"},"PeriodicalIF":5.1,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040504","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":"WTAP suppresses STAT3 via m6A methylation to regulate autophagy and inflammation in central nervous system injury.","authors":"Xiaoyong Zhao, Xiaoli Zhang, Liangzhi Wu, Xiaohe Liu, Yongquan Pan, Taiquan Lv, Mingyang Xu, Kongbin Yang, Xiangyu Wang","doi":"10.1016/j.nbd.2025.106811","DOIUrl":"https://doi.org/10.1016/j.nbd.2025.106811","url":null,"abstract":"<p><p>Central nervous system (CNS) repair after injury is a challenging process limited by inflammation and neuronal apoptosis. This study identifies Wilms' tumor 1-associating protein (WTAP) as a pivotal regulator of neuronal protection and repair through m6A methylation of STAT3 mRNA. By employing spinal cord injury (SCI) as a representative model of CNS injury, transcriptomic analyses reveal WTAP as a key mediator of pathways related to neuronal autophagy and inflammation regulation. WTAP enhances neuronal autophagy by suppressing STAT3 expression and activity, which inhibits the NLRP3 inflammatory pathway. Functional studies demonstrate that WTAP knockdown exacerbates neuronal apoptosis, whereas overexpression improves cell viability, autophagy, and motor recovery. In vivo, WTAP promotes SCI repair via m6A-mediated suppression of STAT3 and regulation of the NLRP3 signaling pathway, highlighting its therapeutic potential for CNS injury repair.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"106811"},"PeriodicalIF":5.1,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040523","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":"Brain acid sphingomyelinase controls addiction-related behaviours in a sex-specific way","authors":"Liubov S. Kalinichenko ,&nbsp;Iulia Zoicas ,&nbsp;Anne-Marie Bienia ,&nbsp;Clara Bühner ,&nbsp;Julia Robinson ,&nbsp;Joshua Kütemeyer ,&nbsp;Annika Labonte ,&nbsp;Thadshajiny Raveendran ,&nbsp;Lena Warth ,&nbsp;Irena Smaga ,&nbsp;Malgorzata Filip ,&nbsp;Volker Eulenburg ,&nbsp;Cosima Rhein ,&nbsp;Anna Fejtova ,&nbsp;Erich Gulbins ,&nbsp;Johannes Kornhuber ,&nbsp;Christian P. Müller","doi":"10.1016/j.nbd.2025.106800","DOIUrl":"10.1016/j.nbd.2025.106800","url":null,"abstract":"<div><div>Addiction is a chronic and severe mental disorder with high gender- and sex-specificity. However, the pathogenesis of this disorder is not fully elucidated, and no targeted pharmacotherapy is available. A growing body of evidence points out the potential involvement of the ceramide system in the pathophysiology of addiction. A pathogenic pathway for several mental disorders based on the overexpression of an enzyme involved in ceramide formation, acid sphingomyelinase (ASM), was recently proposed. Here we show a crucial role of ASM specifically overexpressing in the forebrain for various types of addiction-related behaviours in a drug- and sex-specific way. In male mice, a forebrain ASM overexpression led to enhanced alcohol consumption in a free-choice paradigm. It also diminished the reinforcing properties of alcohol and cocaine, but not that of amphetamine, ketamine, or a natural reinforcer fat/carbohydrate-rich food in the conditioned place preference (CPP) test in males. In female mice, a forebrain ASM overexpression enhanced alcohol binge-like drinking, while moderate alcohol consumption was preserved. ASM overexpression in females contributed to CPP establishment for amphetamine, but not for other psychoactive substances. Altogether, this study shows a specific involvement of forebrain ASM in the development of conditioned reinforcing effects of different types of substances with addictive properties in a sex-specific way. Our data enlarge the current knowledge on the specific molecular mechanisms of dependence from various drugs of abuse and might serve as a basis for the development of drug- and sex-specific targeted therapy.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106800"},"PeriodicalIF":5.1,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008966","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":"Downregulation of the NPY-Y1R system in Grpr neurons results in mechanical and chemical hyperknesis in chronic itch","authors":"Danqing Dai ,&nbsp;Zongxi Li ,&nbsp;Tiantian Zhao,&nbsp;Zhen Li,&nbsp;Yali Tang,&nbsp;Xiujuan Li,&nbsp;Xiao-Fei Gao,&nbsp;Lize Xiong","doi":"10.1016/j.nbd.2025.106806","DOIUrl":"10.1016/j.nbd.2025.106806","url":null,"abstract":"<div><div>Chronic itch remains a clinically challenging condition with limited therapeutic efficacy, posing a significant burden on patients' quality of life. Despite its prevalence, the underlying neural mechanisms remain poorly understood. In this study, we explored the synaptic relationships between neuropeptide Y (NPY) neurons and gastrin-releasing peptide receptor (GRPR) neurons in the spinal cord. Our findings reveal a direct synaptic connection whereby <em>Npy</em> neurons provide inhibitory modulation to <em>Grpr</em> neurons. Notably, during chronic itch, the activity of <em>Grpr</em> neurons was significantly elevated, coinciding with a decrease in Y1 receptor expression and a reduction in both the frequency and amplitude of inhibitory postsynaptic currents (IPSCs). These results suggest a decline in NPY/Y1R system function during chronic itch, leading to a decreased inhibitory influence of <em>Npy</em> neurons on <em>Grpr</em> neurons and subsequent disinhibition and excitation of the latter. This disinhibitory mechanism may underlie the enhanced responsiveness to mechanical and chemical itch stimuli in chronic itch patients.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106806"},"PeriodicalIF":5.1,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008968","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":"Retraction Notice to \"Differential effects of immunotherapy with antibodies targeting α-synuclein oligomers and fibrils in a transgenic model of synucleinopathy\" [Neurobiology of Disease 104 (2017) 85-96].","authors":"Omar El-Agnaf, Cassia Overk, Edward Rockenstein, Michael Mante, Jazmin Florio, Anthony Adame, Nishant Vaikath, Nour Majbour, Seung-Jae Lee, Changyoun Kim, Eliezer Masliah, Robert A Rissman","doi":"10.1016/j.nbd.2025.106788","DOIUrl":"https://doi.org/10.1016/j.nbd.2025.106788","url":null,"abstract":"","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"106788"},"PeriodicalIF":5.1,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008948","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":"Phosphorylated-tau associates with HSV-1 chromatin and correlates with nuclear speckles decondensation in low-density host chromatin regions","authors":"Leonardo D'Aiuto ,&nbsp;Jill K. Caldwell ,&nbsp;Terri G. Edwards ,&nbsp;Chaoming Zhou ,&nbsp;Matthew L. McDonald ,&nbsp;Roberto Di Maio ,&nbsp;Wood A. Joel ,&nbsp;Vanesa R. Hyde ,&nbsp;Callen T. Wallace ,&nbsp;Simon C. Watkins ,&nbsp;Maribeth A. Wesesky ,&nbsp;Or A. Shemesh ,&nbsp;Vishwajit L. Nimgaonkar ,&nbsp;David C. Bloom","doi":"10.1016/j.nbd.2025.106804","DOIUrl":"10.1016/j.nbd.2025.106804","url":null,"abstract":"<div><div>Abnormal tau phosphorylation is a key mechanism in neurodegenerative diseases. Evidence implicates infectious agents, such as Herpes Simplex Virus 1 (HSV-1), as co-factors in the onset or the progression of neurodegenerative diseases, including Alzheimer's disease. This has led to divergence in the field regarding the contribution of viruses in the etiology of neurodegenerative diseases. Research indicates that viruses may function as risk factors driving neurodegenerative disease rather than playing a causative role. Investigating HSV-1 in abnormal tau phosphorylation is important for understanding the role of infectious agents in neurodegeneration.</div><div>We generated cellular models of HSV-1 acute, latent infection, and viral reactivation from latency in cortical brain organoids and investigated the interplay between tau phosphorylation and HSV-1 infection by employing human induced pluripotent stem cell (iPSC)-derived monolayer neuronal cultures and brain organoids. Acute infection with HSV-1 strains 17<em>syn</em>^<em>+</em> and KOS caused nuclear accumulation of phosphorylated tau (p-tau) in neurons and neural precursor cells. Antivirals prevented nuclear accumulation of p-tau. Viral reactivation was accompanied by the nuclear translocation of p-tau. Chromatin immunoprecipitation analysis indicated an interaction of p-tau with the viral chromatin. A reduction in abundance of component of nuclear speckles and their loss of organized morphology in low-denisty host chromatin regions was observed, with strain-specific differences. HSV-1 infection was followed by an increase in the abundance of BRSKs and TAOKs, kinases known to phosphorylate tau.</div><div>These findings show interaction between p-tau and HSV-1 chromatin and demonstrate the ability of HSV-1 to activate mechanisms that are observed in Alzheimer's disease.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106804"},"PeriodicalIF":5.1,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008953","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}