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 ?-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 effectors in primary neuronal cultures derived from male and female AD transgenic mice to investigate the degree to which Gs-PKA signaling selectively promotes the development of AD-like neuropathology after administration of exogenous CRF, CRF1 antagonists, and PKA inhibitors. Further, we will demonstrate the sufficiency of increased Gs-PKA signaling to promote AD-like pathology using a virally mediated Designer Receptors Exclusively Activated by Designer Drugs (DREADD) approach, which specifically increases Gs signaling (AAV- CaMKIIa-HArM3D-IRES-mCitrine), in both male and female tTA:APPsi mice. The similar approach will be used in tTA/APPsi/CRF mice to demonstrate that male-biased ?-arrestin2 signaling is not neuroprotective. Finally, we will perform a quantitative phosphoproteomic assay to identify the sexually dimorphic phosphorylation motifs associated with increased AD-like neuropathology and CRF1 signaling in stressed tTA:APPsi and tTA/APPsi/CRF mice. This study will demonstrate plausible mechanisms that could explain the increased risk of AD in women, and thus provide a mechanistic framework and novel targets for treatments of AD.

Public Health Relevance

The total Alzheimer's patient population is now estimated to be over 45 million worldwide and two thirds of those afflicted are women and yet, very little is known about why women are at such a higher risk. This project will examine how the unique female response to stress, specifically through the CRF1 signaling pathway, contributes to the increased risk for AD. The information derived from this project will help to develop new treatment and prevention strategies that benefit both sexes.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Multi-Year Funded Research Project Grant (RF1)
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Special Emphasis Panel (ZRG1)
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Petanceska, Suzana
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Northwestern University at Chicago
Schools of Medicine
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Yan, Yan; Dominguez, Sky; Fisher, Daniel W et al. (2018) Sex differences in chronic stress responses and Alzheimer's disease. Neurobiol Stress 8:120-126
Dong, Hongxin; Keegan, Jack M; Hong, Ellie et al. (2018) Corticotrophin releasing factor receptor 1 antagonists prevent chronic stress-induced behavioral changes and synapse loss in aged rats. Psychoneuroendocrinology 90:92-101
Fisher, Daniel W; Bennett, David A; Dong, Hongxin (2018) Sexual dimorphism in predisposition to Alzheimer's disease. Neurobiol Aging 70:308-324