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 During stress in females, CRF-Rs normally activate PKA/ERK whereas in males CRF-Rs are withdrawn from the plasma membrane by β-arrestin, so there is significantly less CRF signaling in males.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.

心理应激是阿尔茨海默病(AD)最大的环境危险因素之一。女人 她们比男性更容易受到压力，患上阿尔茨海默病的风险更高。我们的初步数据显示了性行为- 应激对Aβ和tau的依赖效应。在两种不同的急性应激模式中，束缚应激和 掠夺性嗅觉应激，只有女性脑间质液(ISF)Aβ快速而持久地增加 在海马体中的水平，而男性的Aβ没有改变。女性人数的增加受到以下因素的阻碍 抑制CRF受体(CRF-R)。有趣的是，CRF受体在女性和男性身上的信号不同。在.期间 在女性，CRF-R通常激活PKA/ERK，而在男性，CRF-R从 质膜上受β-arrestin调节，所以雄性体内CRF信号明显较少。与此一致 机制，我们的初步数据表明β-arrestin1基因敲除的雄性已经恢复了细胞上的CRF-R 当应激时，ISFAβ水平的增加与雌性几乎相同。我们的数据还表明， Tau对压力的性二型性反应类似。作为对压力的反应，两个男性的ISF tau水平都会增加 和女性，但女性的增幅是男性的4倍。文献表明， 皮质酮是人体内的一种主要应激蛋白，可以增加tau的水平。我们建议， 不同性别的tau反应主要由两种机制驱动：1)不同的CRF-R信号 这导致了性别之间的差异，类似于A和2)两性之间的一种共同机制，即 在皮质酮的推动下，男性和女性的tau水平都有类似的提高。虽然之前的研究已经 在AD中涉及CRF和β-arrestin，这些将是在AD中研究这些途径的第一批研究 压力的设定。 我们假设压力引起性别依赖性的Aβ和tau的增加，这种增加是由 CRF-R/β-arrestin信号转导，以及皮质酮对tau的非性别影响。我们 建议确定男性和女性在急性应激中激活的信号通路 对A、β和tau水平进行不同的调控。我们还将对CRF或CRF改变的小鼠造成慢性压力 皮质酮(CORT)信号或缺乏β-arrestin的表达，以确定对行为和病理的影响。 我们的前提是，确定不同性别之间的细胞通路可以识别出 发展阿尔茨海默病，并导致基于性别的治疗方法，专门调节阿尔茨海默病的应激反应。