Sex differences in central stress response and Alzheimer's disease neuropathology

摘要 临床研究表明，阿尔茨海默病（AD）对女性的影响更大 但这种性别差异背后的生物学机制并不清楚， 明白我们小组和其他人的一致发现表明，压力有助于 通过影响促肾上腺皮质激素释放因子（CRF）的传递来研究AD的发病机制。 近年来我们发现，在应激状态下，CRF通过激活第二信使而实现功能转换 通过CRF受体1（CRF 1）的信号传导有利于女性中的Gs-PKA信号传导，而β- 抑制蛋白-2信号传导在男性中是有利的。CRF 1信号传导中的这种性别偏见可能导致不同的 已知驱动AD神经病理学的下游靶点之间的磷酸化模式， 为不同性别的AD风险差异提供了一种机制性解释。符合本 机制，我们的初步数据表明，淀粉样斑块的发展是更大的 在雌性比雄性转基因小鼠中，人APP和前脑限制性CRF均 过表达（APP+/CRF+/tTA+小鼠）为了继续这一系列工作，在本补充中，我们 将研究精神疾病中性别差异的分子和细胞机制。 与AD发病机制相关的疾病，并确定可能有助于 解释为什么压力对女性的影响不同。多样性补充中提出的项目 与资助的母基金直接相关（1 RF 1 AG 057884）。我们假设慢性压力 增加了雌性转基因小鼠中AD神经病理学的风险，这是由于雌性转基因小鼠中的性二态性。 下游CRF 1信号通路和由此产生的AD相关蛋白磷酸化， 可能是可逆的特异性CRF 1拮抗剂或PKA抑制剂。为了验证我们的假设，我们 将证实急性和慢性AD后小鼠模型中的性别差异神经发病机制 应力我们将测试记忆和焦虑抑郁样行为以及生化 测定APP/PS1小鼠在慢性社会应激下的性别特异性脆弱性的措施 隔离应激和急性束缚应激。然后我们将确定性别特异性机制 CRF信号传导对AD病理学的影响。我们将使用病毒载体， CRF在APP/PS1小鼠的脑区特异性的方式，以确定如何上述 道路受到影响。在被病毒操纵的区域中，前额叶皮层和 海马将被靶向以确定CRF 1的性别特异性下游效应。 体内信号传导最后，我们将专门操纵这些通路（PKA或β-arrestin-2）。 这项研究将证明合理的机制，可以解释AD的风险增加， 女性，并因此提供了一个机制框架和新的目标治疗AD。

Abstract 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 β- arrestin-2 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 both human APP and forebrain-restricted CRF are overexpressed (APP+/CRF+/tTA+ mice) To continue this line of work, in this supplement, we will study the molecular and cellular mechanisms underlying sex differences in psychiatric disorders linked to AD pathogenesis and identifying the signaling pathways that may help explain why stress affects females differently. The project proposed in the diversity supplement directly ties to the funded parent grant (1 RF1 AG057884). 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 confirm sex-divergent neuropathogenesis in mouse models of AD after acute and chronic stress. We will test the memory and anxiety-depressive-like behaviors and biochemical measures to determine the sex-specific vulnerability in APP/PS1 mice under chronic social isolation stress and acute restraint stress. Then we will determine the sex-specific mechanistic effects of CRF signaling impact on AD pathology. We will use viral vectors that overexpress CRF in APP/PS1 mice in a brain area-specific manner to determine how the aforementioned pathways are affected. Among the areas to be virally manipulated, the prefrontal cortex and hippocampus will be targeted to determine the sex-specific downstream effects of CRF1 signaling in vivo. Finally, we will manipulate these pathways (PKA or β-arrestin-2) specifically. 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.