Alzheimer's disease; tauopathy; THY-Tau22 mouse model; sex differences; age differences; single-cell RNA sequencing; transcriptomics
Abstract :
[en] Background: Tauopathies, including Alzheimer's disease (AD) and frontotemporal dementia (FTD), display sex-specific differences in prevalence and progression, but the underlying molecular mechanisms remain unclear. Single-cell transcriptomic analysis of animal models can reveal how AD pathology affects different cell types across sex and age.
Objective: To understand sex-specific and sex-dimorphic transcriptomic changes in different cell types and their age-dependence in the THY-Tau22 mouse model of AD-linked tauopathy.
Methods: We applied single-cell RNA sequencing (scRNA-seq) to cortical tissue from male and female THY-Tau22 and wild-type mice at 17 months of age, when they had prominent tau inclusion pathology, and compared the results with corresponding data previously obtained at 7 months of age. Using differential statistical analysis for individual genes, pathways, and gene regulatory networks, we identified sex-specific, sex-dimorphic, and sex-neutral changes, and looked at how they evolved over age. To validate the most robust findings across distinct mouse models and species, the results were compared with cortical scRNA-seq data from the transgenic hAPP-based Tg2576 mouse model and human AD.
Results: We identified several significant sex-specific and sex-dimorphic differentially expressed genes in neurons, microglia, astrocytes and oligodendrocytes, including both cross-sectional changes and alterations from 7 months to 17 months of age. Key pathways affected in a sex-dependent manner across age included neurotransmitter signaling, RNA processing and splicing, stress response pathways, and protein degradation pathways. In addition, network analysis revealed the AD-associated genes Clu, Mbp, Fos and Junb as relevant regulatory hubs. Analysis of age-dependent changes highlighted genes and pathways associated with inflammatory response (Malat1, Cx3cr1), protein homeostasis (Cst3), and myelin maintenance (Plp1, Cldn11, Mal), that showed consistent sex-dependent changes as the THY-Tau22 mice aged. Multiple genes with established implications in AD, including the long non-coding RNA gene Malat1, displayed concordant sex-specific changes in mouse models and human AD.
Conclusions: This study provides a comprehensive single-cell transcriptomic characterization of sex-linked and age-dependent changes in the THY-Tau22 tauopathy model, revealing new insights into the interplay between age-dependent AD-like pathologies and sex. The identified sex-specific changes and their conservation across models and human AD highlight molecular targets for further preclinical investigation of sex-specific therapeutic strategies in AD.
Research center :
Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group)
Disciplines :
Neurology Human health sciences: Multidisciplinary, general & others Biotechnology Life sciences: Multidisciplinary, general & others
Author, co-author :
Ali, Muhammad
Garcia, Pierre
Lunkes, Laetitia P.
Sciortino, Alessia
Thomas, Melanie
Heurtaux, Tony
Grzyb, Kamil
Halder, Rashi
Skupin, Alex
Buée, Luc
Blum, David
Buttini, Manuel
GLAAB, Enrico ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Biomedical Data Science
Temporal Transcriptomic Changes in the THY-Tau22 Mouse Model of Tauopathy Display Cell Type- and Sex-Specific Differences
Publication date :
2025
Journal title :
Acta Neuropathologica Communications
eISSN :
2051-5960
Volume :
in press
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
Development Goals :
3. Good health and well-being
FnR Project :
FNR17027921 - PreDYT - Predictive Biomarkers In Dystonia: Defining The Paradigm Of Monogenic Dystonia To Implement The Diagnosis And Prognosis Of Undiagnosed Forms, 2022 (01/07/2023-30/06/2026) - Enrico Glaab
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