Single cell transcriptomic changes in the THY-Tau22 mouse model of Alzheimer's disease at 17 months of age

Alzheimer's disease (AD) displays sex-specific differences in prevalence and progression, but the underlying molecular mechanisms remain unclear. To investigate sex-dependent molecular changes associated with tau pathology at a late disease stage, we performed single-cell RNA sequencing on cortical tissue from 17-month-old THY-Tau22 mice and wildtype littermates of both sexes. The analysis revealed extensive sex-specific and sex-dimorphic transcriptomic alterations across multiple cell types, with particularly pronounced changes in microglia and oligodendrocytes. Key pathways affected in a sex-dependent manner included RNA processing and splicing, stress response pathways, neurotransmitter signaling, and protein degradation pathways. Network analysis identified the genes Clu, Mbp, Fos and Junb as potential regulatory hubs. Multiple genes with established implications in AD, including the long non-coding RNA gene MALAT1, showed concordant sex-specific changes when compared with both earlier time points and human AD data. This study provides a comprehensive characterization of sex-dependent transcriptomic changes in late-stage tau pathology, revealing new insights into the interplay between AD-like pathology and biological sex. Overall design: The study investigated transcriptomic changes in the THY-Tau22 mouse model, which expresses human 4-repeat tau with G272V and P301S mutations under control of the neuronal Thy1.2 promoter. Single-cell paired-end RNA sequencing analysis was conducted on cortical tissue from mice at 17 months of age, representing a late disease stage. The experimental design included four groups with balanced sex distribution: male THY-Tau22 transgenic mice (n=4), male wildtype littermates (n=4), female THY-Tau22 transgenic mice (n=5), and female wildtype littermates (n=3). This late-stage analysis builds upon and complements previously published data from the same model at 7 months of age (GSE245035), enabling longitudinal assessment of disease progression and sex-dependent molecular changes.