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

心理应激是阿尔茨海默病（AD）最大的环境危险因素之一。妇女 比男性更容易受到压力，患AD的风险也更高。我们的初步数据显示- 应力对Aβ和tau的依赖性影响。在两种不同的急性应激模型中，束缚应激和 在捕食性嗅觉应激中，只有雌性大鼠脑间质液（ISF）Aβ水平快速而持续地升高， 海马体中的A β水平，而男性中的Aβ没有变化。女性的增长受到以下因素的阻碍 抑制CRF受体（CRF-R）。有趣的是，CRF-R在女性和男性中发出不同的信号。期间 在女性应激时，CRF-R通常激活PKA/ERK，而在男性中，CRF-R从 细胞膜上，因此在雄性中CRF信号传导显著较少。符合本 我们的初步数据表明，β-arrestin 1基因敲除的雄性动物细胞上的CRF-Rs恢复了 表面，当应激时，ISF Aβ水平几乎与雌性相同地增加。我们的数据还表明， tau蛋白对应激的类似性二型反应。作为对压力的反应，两种雄性的ISF tau水平都增加， 而女性，则比男性多出4倍。文献表明， 皮质酮是一种遍布全身的主要应激蛋白，它可以增加tau水平。我们建议 在每种性别中不同的tau应答主要由两种机制驱动：1）不同的CRF-R信号传导 导致两性之间差异的原因，类似于A和2）两性的共同机制， 由皮质酮驱动，以增加男性和女性的tau水平。虽然先前研究已 提示CRF和β-arrestin与AD有关，这些将是研究AD中这些通路的首批研究， 压力的设置。 我们假设压力导致Aβ和tau蛋白的性别依赖性增加，这是由 CRF-R/β-arrestin信号传导，以及对皮质酮驱动的tau蛋白的性别无关效应。我们 建议确定男性和女性急性应激激活的信号通路， 不同地调节Aβ和tau水平。我们还将对改变了CRF的小鼠进行慢性应激， 皮质酮（CORT）信号传导或缺乏β-抑制蛋白表达以确定对行为和病理学的影响。 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AD，并导致基于性别特异性调节AD中的应激反应的治疗。

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 During stress in females, CRF-Rs normally activate PKA/ERK whereas in males CRF-Rs are withdrawn from the plasma membrane by β-arrestin, so there is significantly less CRF signaling in males.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