Sex Differences in Central Stress Response and Alzheimer's Disease Neuropathology

Clinical studies indicate that Alzheimer’s disease (AD) disproportionately affects women more than men, but the biological mechanisms underlying this sexual divergence are not well understood. Convergent findings from our group and others indicate that stress contributes to the pathogenesis of AD through its effects on corticotrophin releasing factor (CRF) transmission. Recently we found that during stress, CRF coverts its function by triggering second messenger signaling through the CRF receptor 1 (CRF1) favoring Gs-PKA signaling in females, while β-arrestin2 signaling is favored in males. This sex bias in CRF1 signaling likely results in different phosphorylation patterns among downstream targets known to drive AD neuropathology and so provides one mechanistic explanation for the difference in AD risk by sex. Consistent with this mechanism, our preliminary data demonstrate that amyloid plaque development is much greater in female than male transgenic mice, in which human APP with Tg2576 mice background and forebrain CRF are overexpressed (named TT mice). We hypothesize that chronic stress increases the risk of AD neuropathology in female transgenic mice due to sexual dimorphism in downstream CRF1 signaling pathways and resultant AD related-protein phosphorylation, which may be reversible with specific CRF1 antagonists or PKA inhibitors. To test our hypothesis, we will utilize a transgenic mouse model of AD that displays no sex-specific difference in AD neuropathology under non-stressed conditions (tTA:APPsi mouse strain). First, using two independent stress paradigms, chronic unpredictable stress to tTA:APPsi mice and genetically forebrain-restricted CRF overexpression by creating tTA/APPsi/CRF mice, we will compare that amyloid pathology and cognitive deficits are increased in females compared to males during stress and that antagonism of CRF1 signaling is able to reduce these pathologies in a sex-dependent manner. Then, we will interrogate CRF1’s downstream