{"title":"Differential effects of age and sex on tau pathology propagation in the htau mouse model: A neuropathological and proteomic study","authors":"Andreea-Claudia Kosa, Lidia Lopez-Gutierrez, Kunie Ando, Emilie Doeraene, Emmanuel Aydin, Hinde Lasri, Alain Wathelet-Depauw, Karlien Pieters, David Van Morckhoven, Virginie Imbault, Christine Dubois, Xavier Bisteau, Basile Stamatopoulos, Mariana Igoillo-Esteve, Jean-Pierre Brion, Karelle Leroy","doi":"10.1002/alz.70784","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> INTRODUCTION</h3>\n \n <p>Aging is the main risk factor for Alzheimer's disease (AD), acting through still poorly understood mechanisms. AD is associated with the development of a tau pathology, a hallmark lesion propagating in the brain along neuroanatomically connected pathways. This study investigates changes in gene expression and patterns of tau pathology after induction of tau pathology propagation and the effects of age and sex on this propagation.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>Young and old humanized htau mice were intracerebrally injected with pathological tau from human AD brain to induce tau pathology.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>Young and old htau male mice showed similar patterns of tau pathology propagation, whereas the density of tau pathology was increased in young compared to old female mice. Proteomic analysis demonstrated differential expression of proteins involved in endocytosis, autophagosome formation, and tau splicing.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>The increased tau pathology formation in young female mice suggests that involvement of selected biological mechanisms could occur early in women during their midlife to explain their sensitivity to the development of tau pathology.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>Tau pathology induced by human PHF-tau is mainly composed of 3R-tau in htau mice.</li>\n \n <li>Splicing factors favoring 4R-tau are downregulated in mice with tau pathology.</li>\n \n <li>Tau pathology propagation is increased in young females compared to old females.</li>\n \n <li>Proteins implicated in endocytosis and autophagy are modified when tau pathology propagates.</li>\n \n <li>Some protein expressions are similarly modified in young females and during normal aging.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 10","pages":""},"PeriodicalIF":11.1000,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12516240/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Alzheimer's & Dementia","FirstCategoryId":"3","ListUrlMain":"https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.70784","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
INTRODUCTION
Aging is the main risk factor for Alzheimer's disease (AD), acting through still poorly understood mechanisms. AD is associated with the development of a tau pathology, a hallmark lesion propagating in the brain along neuroanatomically connected pathways. This study investigates changes in gene expression and patterns of tau pathology after induction of tau pathology propagation and the effects of age and sex on this propagation.
METHODS
Young and old humanized htau mice were intracerebrally injected with pathological tau from human AD brain to induce tau pathology.
RESULTS
Young and old htau male mice showed similar patterns of tau pathology propagation, whereas the density of tau pathology was increased in young compared to old female mice. Proteomic analysis demonstrated differential expression of proteins involved in endocytosis, autophagosome formation, and tau splicing.
DISCUSSION
The increased tau pathology formation in young female mice suggests that involvement of selected biological mechanisms could occur early in women during their midlife to explain their sensitivity to the development of tau pathology.
Highlights
Tau pathology induced by human PHF-tau is mainly composed of 3R-tau in htau mice.
Splicing factors favoring 4R-tau are downregulated in mice with tau pathology.
Tau pathology propagation is increased in young females compared to old females.
Proteins implicated in endocytosis and autophagy are modified when tau pathology propagates.
Some protein expressions are similarly modified in young females and during normal aging.
期刊介绍：
Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.
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