The convergence of stress and sex on Abeta and tau metabolism and pathology

压力和性对 Abeta 和 tau 代谢及病理学的影响

• 批准号: 10734280
• 负责人: John R Cirrito
• 金额: $ 213.31万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734280
• 关键词: APP-PS1; Acute; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Model; Arrestins; Behavior; Blocking Antibodies; Brain; Cell Surface Receptors; Cell membrane; Cell surface; Chronic; Chronic stress; Corticosterone; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Coupled; Cyclic AMP-Dependent Protein Kinases; Data; Disparate; Environmental Risk Factor; Female; G alpha q Protein; Generations; Genetic; Glucocorticoid Receptor; Heat shock proteins; Hippocampus; Hour; Individual; Intercellular Fluid; Knock-out; Knockout Mice; Literature; Long-Term Effects; Mediating; Metabolism; Microdialysis; Modeling; Monitor; Mus; Pathology; Pathway interactions; Play; Process; Proteins; Psychological Stress; Receptor Signaling; Regulation; Reporting; Risk; Risk Factors; Role; Sex Differences; Signal Pathway; Signal Transduction; Stress; Synapses; Therapeutic; Transgenic Mice; Transgenic Organisms; Traumatic Brain Injury; United States; Viral; Woman; Work; acute stress; beta-arrestin; biological adaptation to stress; epidemiology study; high risk; in vivo; male; men; response; restraint stress; secretase; sex; sexual dimorphism; sleep abnormalities; stress related disorder; tau Proteins

Psychological stress is one of the largest environmental risk factors for Alzheimer’s disease (AD). Women are more prone to stress and are at higher risk of AD than men. Our preliminary data demonstrate a sex- dependent effect of stress on both Aβ and tau. In two distinct models of acute stress, restraint stress and predatory olfactory stress, only females have a rapid and prolonged increase in brain interstitial fluid (ISF) Aβ levels in the hippocampus, whereas Aβ in males does not change. The increase in females is blocked by inhibiting the CRF receptor (CRF-R). Interestingly, CRF-Rs signal differently in females and males. During stress in females, CRF-Rs normally activate PKA/ERK whereas in males CRF-Rs are withdrawn from the plasma membrane by β-arrestin, so there is significantly less CRF signaling in males. Consistent with this mechanism, our preliminary data demonstrates β-arrestin1 knockout males have restored CRF-Rs on the cell surface, and when stressed ISF Aβ levels increase nearly identically to females. Our data also demonstrate a similar sexual dimorphic response to stress for tau. In response to stress, ISF tau levels increase in both males and females, but females have a 4-fold greater increase than males. The literature demonstrates that corticosterone, a main stress protein throughout the body, can increase tau levels. We propose that the disparate tau responses in each sex are primarily driven by two mechanisms: 1) differential CRF-R signaling that drives the difference between the sexes, similar to A and 2) a common mechanism in both sexes that is driven by corticosterone to increase tau levels similarly in males and females. While previous studies have implicated CRF and β-arrestin in AD, these will be some of the first studies studying these pathways in AD in the setting of stress. We hypothesize that stress causes sex-dependent increases on Aβ and tau that are mediated by CRF-R/β-arrestin signaling, as well as sex-independent effects on tau driven by corticosterone. We propose to determine the signaling pathways that are activated by acute stress in males and females to regulate Aβ and tau levels differently. We will also chronically stress mice that have altered CRF or corticosterone (cort) signaling or lack β-arrestin expression to determine effects on behavior and pathology. Our premise is that determining the cellular pathways that differ between the sexes could identify risks of developing AD and lead to therapeutics to specifically modulate the stress response in AD based on sex.

心理压力是阿尔茨海默病（AD）最大的环境危险因素之一。女性