Cross-Species Single-Cell Analysis Reveals Sex Differences in Mitochondrial Dysfunction as a Conserved Feature of Tau Pathology

ABSTRACT: Tau pathology represents one of the main hallmarks of Alzheimer's disease (AD), with previous studies reporting significant sex differences in tau accumulation and disease progression. While the Tau P301L zebrafish model has emerged as a promising tool for studying tauopathy, it has not been systematically compared to human AD at the single-cell level, particularly regarding sex-dependent molecular alterations that could validate its translational relevance. This study aimed to characterize the molecular and cellular pathogenesis of the Tau P301L zebrafish model using single-cell transcriptomics to reveal cell-type-specific and sex-dimorphic responses to tau pathology and confirm its relevance through comparison to human AD and the THY-Tau22 mouse model. We performed single-nucleus RNA sequencing on brain tissue from 6-month-old Tau P301L transgenic and wild-type zebrafish, analyzing differential gene expression across major brain cell types with sex-specific resolution. Cross-species comparisons with single-cell mouse and human AD datasets were performed through gene, pathway, and network-level analyses. Our analysis revealed sex-dimorphic patterns of mitochondrial dysfunction, where electron transport chain genes showed opposite tau-associated expression alterations between males and females across multiple cell types. The comprehensive single-cell characterization of the Tau P301L zebrafish supports the utility of this model for translational AD research and demonstrates that sex-specific mitochondrial responses represent cross-species conserved pathological mechanisms with important implications for personalized therapeutic strategies.

ORGANISM(S): Danio rerio

PROVIDER: GSE310345 | GEO | 2025/12/10

REPOSITORIES: GEO