Temporal transcriptomic changes in the THY-Tau22 mouse model of tauopathy display cell type- and sex-specific differences
Abstract 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 pathol...
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BMC
2025-05-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | https://doi.org/10.1186/s40478-025-02013-z |
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| author | Muhammad Ali Pierre Garcia Laetitia P. Lunkes Alessia Sciortino Melanie H. Thomas Tony Heurtaux Kamil Grzyb Rashi Halder Alexander Skupin Luc Buée David Blum Manuel Buttini Enrico Glaab |
| author_facet | Muhammad Ali Pierre Garcia Laetitia P. Lunkes Alessia Sciortino Melanie H. Thomas Tony Heurtaux Kamil Grzyb Rashi Halder Alexander Skupin Luc Buée David Blum Manuel Buttini Enrico Glaab |
| author_sort | Muhammad Ali |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-9258a3ce57b84b058e95baad7f73fac3 |
| institution | Kabale University |
| issn | 2051-5960 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
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| series | Acta Neuropathologica Communications |
| spelling | doaj-art-9258a3ce57b84b058e95baad7f73fac32025-08-20T03:53:16ZengBMCActa Neuropathologica Communications2051-59602025-05-0113112710.1186/s40478-025-02013-zTemporal transcriptomic changes in the THY-Tau22 mouse model of tauopathy display cell type- and sex-specific differencesMuhammad Ali0Pierre Garcia1Laetitia P. Lunkes2Alessia Sciortino3Melanie H. Thomas4Tony Heurtaux5Kamil Grzyb6Rashi Halder7Alexander Skupin8Luc Buée9David Blum10Manuel Buttini11Enrico Glaab12Luxembourg Centre for Systems Biomedicine (LCSB), University of LuxembourgLuxembourg Centre for Systems Biomedicine (LCSB), University of LuxembourgLuxembourg Centre for Systems Biomedicine (LCSB), University of LuxembourgLuxembourg Centre for Systems Biomedicine (LCSB), University of LuxembourgLuxembourg Centre for Systems Biomedicine (LCSB), University of LuxembourgDepartment of Life Sciences and Medicine (DLSM), University of LuxembourgLuxembourg Centre for Systems Biomedicine (LCSB), University of LuxembourgLuxembourg Centre for Systems Biomedicine (LCSB), University of LuxembourgLuxembourg Centre for Systems Biomedicine (LCSB), University of LuxembourgLille Neuroscience & Cognition, University of Lille, Inserm, CHU Lille, Alzheimer & Tauopathies, LabEx DISTALZLille Neuroscience & Cognition, University of Lille, Inserm, CHU Lille, Alzheimer & Tauopathies, LabEx DISTALZLuxembourg Centre for Systems Biomedicine (LCSB), University of LuxembourgLuxembourg Centre for Systems Biomedicine (LCSB), University of LuxembourgAbstract 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.https://doi.org/10.1186/s40478-025-02013-zAlzheimer's diseaseTauopathyTHY-Tau22 mouse modelSex differencesAge differencesSingle-cell RNA sequencing |
| spellingShingle | Muhammad Ali Pierre Garcia Laetitia P. Lunkes Alessia Sciortino Melanie H. Thomas Tony Heurtaux Kamil Grzyb Rashi Halder Alexander Skupin Luc Buée David Blum Manuel Buttini Enrico Glaab Temporal transcriptomic changes in the THY-Tau22 mouse model of tauopathy display cell type- and sex-specific differences Acta Neuropathologica Communications Alzheimer's disease Tauopathy THY-Tau22 mouse model Sex differences Age differences Single-cell RNA sequencing |
| title | Temporal transcriptomic changes in the THY-Tau22 mouse model of tauopathy display cell type- and sex-specific differences |
| title_full | Temporal transcriptomic changes in the THY-Tau22 mouse model of tauopathy display cell type- and sex-specific differences |
| title_fullStr | Temporal transcriptomic changes in the THY-Tau22 mouse model of tauopathy display cell type- and sex-specific differences |
| title_full_unstemmed | Temporal transcriptomic changes in the THY-Tau22 mouse model of tauopathy display cell type- and sex-specific differences |
| title_short | Temporal transcriptomic changes in the THY-Tau22 mouse model of tauopathy display cell type- and sex-specific differences |
| title_sort | temporal transcriptomic changes in the thy tau22 mouse model of tauopathy display cell type and sex specific differences |
| topic | Alzheimer's disease Tauopathy THY-Tau22 mouse model Sex differences Age differences Single-cell RNA sequencing |
| url | https://doi.org/10.1186/s40478-025-02013-z |
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