Single-cell transcriptional profiling and gene regulatory network modeling in Tg2576 mice reveal gender-dependent molecular features preceding Alzheimer-like pathologies

To identify disease-related molecular processes that occur before the onset of detectable neuropathology in Alzheimer's disease (AD), we performed a comprehensive single-cell analysis of disease-related molecular sex differences in transcriptomic data from the neocortex of 24-week-old Tg2576 mice and wild-type littermate controls. Cell type-specific changes were investigated at the level of individual genes, pathways and gene regulatory networks. The analyses revealed significant cell-type-specific gene expression changes in individual genes, pathways and sub-networks, including sex-specific and sex-dimorphic changes in both upstream transcription factors and their downstream targets, before the onset of overt disease. The study opens a window into the molecular events that may determine sex-specific susceptibility to Alzheimer's disease and uncovers tractable target candidates for potential sex-specific precision medicine for AD. Overall design: The study used the Tg2576 transgenic mouse model of Alzheimer's disease, which overexpresses human APP with the Swedish mutation. Single-cell RNA-seq was performed on neocortical samples from 24-week-old Tg2576 mice and wildtype littermate controls using the DropSeq approach. The experimental conditions compared were: Tg2576 transgenic males, Wildtype control males, Tg2576 transgenic females, and Wildtype control females (9 mice per genotype/gender, using barcoded pooled replicates with four sample pools, one for each condition and gender).