Sex Differences in the Phosphoproteomic Profiles of APP/PS1 Mice after Chronic Unpredictable Mild Stress.

Approximately two-thirds of those suffering with Alzheimer's disease (AD) are women, however, the biological mechanisms underlying this sex divergence of AD prevalence remain unknown. Previous research has shown sex-specific biochemical differences that bias female mice toward pro-AD signaling on the phosphoproteomic level via corticotropin releasing factor (CRF) receptor 1 activation after CRF overexpression. Here we aimed to determine if chronic stress would induce a similar response in AD mouse models. We stressed 4-month-old APP/PS1 mice using a chronic unpredictable mild stress (CUMS) paradigm for up to 1 month. Following CUMS and behavioral assessments, we quantified whole protein and phosphoprotein levels in the cortex of stressed and non-stressed APP/PS1 mice using mass spectrometry-based proteomics. While there were no statistically significant differences at the total protein and peptide abundance levels, we found 909 and 841 statistically significant phosphopeptides between stressed and unstressed females and males, respectively, using a false discovery rate of 5%. Of these significant phosphopeptides, only 301 were the same in males and females. These results indicate that while both males and females undergo protein phosphorylation changes following stress, the peptides that are phosphorylated differ between sexes. We then used Metacore analysis to determine which biological pathways were affected. We found that several pathways were changed differently between male and female mice including NMDA receptor trafficking, cytoskeleton organization, and tau pathology. The differing biological pathways affected between males and females in response to chronic stress may help us to better understand why women are at a higher risk of AD.