Sex-Dependent Alterations of Apoptotic Processes in Alzheimer’s Disease Revealed by Large-Scale Single-Cell Transcriptomics#

Authors#

Mohamed Soudy, Sophie Le Bars, Enrico Glaab

Abstract#

Introduction#

This study investigates the sex differences in Alzheimer’s disease by analyzing a large-scale single-cell transcriptomic atlas of the human prefrontal cortex. The research uncovers distinct, sex-dependent alterations in apoptotic and cell death processes across various cell types, with significant changes observed in regulatory pathways involving genes like SGK3, ERBB4, and RPTOR.

Methods#

We conducted systems-level bioinformatics analyses on a large-scale single-cell transcriptomic atlas of Alzheimer’s disease, derived from 427 human prefrontal cortex samples with varying AD pathology. This approach included building cell type-specific and sex-specific differential expression, pathway analysis, gene regulatory networks and cell-cell communication to identify sex-dependent changes in the data.

Results#

The study revealed significant sex-dependent differences in Alzheimer’s disease, with distinct alterations in apoptotic and cell death pathways across various cell types. In male astrocytes, the gene RPTOR was identified as a key regulator of apoptosis through the mTOR pathway, driving sex-specific expression changes. Conversely, female astrocytes and neurons exhibited unique changes in Wnt signaling, cell cycle regulation, and tyrosine phosphorylation pathways, highlighting the complex role of sex-specific molecular mechanisms in Alzheimer’s disease.

Discussion#

This study underscores the importance of sex-specific molecular mechanisms in Alzheimer’s disease, particularly highlighting RPTOR as a key male-specific regulator in astrocytes, which may inform future research and therapeutic strategies.