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 During stress in females, CRF-Rs normally activate PKA/ERK whereas in males CRF-Rs are withdrawn from the plasma membrane by β-arrestin, so there is significantly less CRF signaling in males.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氏病（AD）最大的环境危险因素之一。女性 比男性更容易承受压力，并且广告风险更高。我们的初步数据证明了性别 压力对Aβ和TAU的依赖性。在两个不同的急性应力模型中，约束压力和 掠食性嗅觉应激，只有女性的脑间隙液（ISF）Aβ的迅速增加且长期增加 海马中的水平，而男性的Aβ不会改变。女性的增加被 抑制CRF受体（CRF-R）。有趣的是，在女性和男性中，CRF-RS信号不同。期间 女性的压力，CRF-R通常会激活PKA/ERK，而在男性中，CRF-RS撤回了 β-arrestin的质膜，因此雄性的CRF信号明显降低。与此一致 机制，我们的初步数据表明β-arrestin1敲除雄性已恢复了细胞上的CRF-RS 表面，当压力时，ISFAβ水平几乎增加到女性。我们的数据也证明了 对Tau的压力的类似性二态反应。响应压力，两名男性的ISF tau水平都会增加 和女性，但女性比男性增加4倍。文献表明 皮质酮是整个体内的主要应激蛋白，可以提高tau水平。我们建议 每种性别中的不同tau反应主要由两种机制驱动：1）差异CRF-R信号传导 驱动性别之间的差异，类似于A和2）两性中的共同机制 由皮质酮驱动，在男性和女性中类似地提高TAU水平。以前的研究有 在AD中暗示了CRF和β-arrestin，这些将是研究AD中这些途径的一些最早的研究 压力的设置。 我们假设压力会导致性别依赖性的Aβ和TAU增加，而Aβ和TAU介导 CRF-R/β-arrestin信号传导以及对皮质酮驱动的TAU的独立影响。我们 建议确定男性和女性急性应激激活的信号传导途径 调节Aβ和tau水平不同。我们还将慢性应力小鼠改变CRF或 皮质酮（CORT）信号传导或缺乏β-arrestin表达，以确定对行为和病理的影响。 我们的前提是，确定性别之间不同的细胞途径可以识别 开发AD并导致治疗，以根据性别特别调节AD中的压力反应。