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

中枢应激反应和阿尔茨海默病神经病理学的性别差异

• 批准号: 9924147
• 负责人: Hongxin Dong
• 金额: $ 15.01万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924147
• 关键词: APP-PS1; Acute; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Anxiety; Area; Behavior; Biochemical; Biological; Brain; CRF receptor type 1; Chronic; Chronic stress; Clinical Research; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Cyclic AMP-Dependent Protein Kinases; Data; Development; Female; Funding; Hippocampus (Brain); Human; Link; Measures; Memory; Mental disorders; Molecular; Mus; Neuropathogenesis; PKA inhibitor; Pathogenesis; Pathology; Pathway interactions; Pattern; Phosphorylation; Prefrontal Cortex; Prevention strategy; Prosencephalon; Second Messenger Systems; Senile Plaques; Sex Bias; Sex Differences; Signal Pathway; Signal Transduction; Social isolation; Stress; Testing; Transgenic Mice; Viral; Viral Vector; Woman; Work; acute stress; arrestin 2; beta-arrestin; biological adaptation to stress; depressive symptoms; high risk; in vivo; male; men; mouse model; neuropathology; novel; overexpression; parent grant; patient population; response; restraint stress; sex; sexual dimorphism; transmission process; treatment strategy

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.

抽象的 临床研究表明，阿尔茨海默氏病（AD）不成比例地影响女性 比男人，但是这种性差异的生物学机制不好 理解。来自我们小组和其他人的收敛发现表明压力有助于 AD通过其对皮质营养蛋白释放因子（CRF）传播的影响。 最近，我们发现在压力下，CRF通过触发第二使者来涵盖其功能 通过CRF受体1（CRF1）信号传导有利于女性GS-PKA信号传导，而β- 雄性逮捕蛋白2信号传导受到青睐。 CRF1信号中的性偏见可能导致不同 已知驱动AD神经病理学等的下游靶标之间的磷酸化模式等 提供了一个机械解释，以说明性别差异。与此一致 机制，我们的初步数据表明淀粉样蛋白斑块的发展要大得多 在雌性中，人类应用和限制性CRF的男性转基因小鼠是 过表达（app+/crf+/tta+小鼠）要继续这项工作，在此补充中，我们 将研究精神病性别差异的分子和细胞机制 与AD发病机理相关的疾病并识别可能有助于的信号传导途径 解释压力为什么对女性的影响有所不同。该项目在多样性补充中提出 直接与资助的父母赠款（1 RF1 AG057884）联系。我们假设慢性压力 由于性二态性，增加了女性转基因小鼠AD神经病理学的风险 下游CRF1信号通路和由此产生的AD相关蛋白磷酸化，它们 特定的CRF1拮抗剂或PKA抑制剂可能可逆。为了检验我们的假设，我们 急性和慢性后，将确认在AD的小鼠模型中确认性传播的神经病发生 压力。我们将测试记忆和焦虑抑郁症状的行为和生化 在慢性社会下确定APP/PS1小鼠的性别特定脆弱性的措施 隔离应力和急性约束应力。然后，我们将确定性别特定的机械 CRF信号对AD病理的影响。我们将使用过表达的病毒向量 APP/PS1小鼠的CRF以大脑区域特异性的方式确定近似 途径受到影响。在几乎要操纵的区域中，前额叶皮层和 海马将被针对确定CRF1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途径（PKA或β-arrestin-2）。 这项研究将证明合理的机制，可以解释AD在 妇女，因此为AD治疗提供了一个机械框架和新颖的目标。

项目成果

Sex differences in CRF1, CRF, and CRFBP expression in C57BL/6J mouse brain across the lifespan and in response to acute stress.

• DOI: 10.1111/jnc.15157
• 发表时间: 2021-08
• 期刊: JOURNAL OF NEUROCHEMISTRY
• 影响因子: 4.7
• 作者: Locci, Andrea;Yan, Yan;Rodriguez, Guadalupe;Dong, Hongxin
• 通讯作者: Dong, Hongxin

Sex Differences in the Phosphoproteomic Profiles of APP/PS1 Mice after Chronic Unpredictable Mild Stress.

• DOI: 10.3233/jad-191009
• 发表时间: 2020
• 期刊: JOURNAL OF ALZHEIMERS DISEASE
• 影响因子: 4
• 作者: Dominguez, Sky;Rodriguez, Guadalupe;Fazelinia, Hossein;Ding, Hua;Spruce, Lynn;Seeholzer, Steven H.;Dong, Hongxin
• 通讯作者: Dong, Hongxin

Corticotrophin releasing factor receptor 1 antagonists prevent chronic stress-induced behavioral changes and synapse loss in aged rats.

• DOI: 10.1016/j.psyneuen.2018.02.013
• 发表时间: 2018-04
• 期刊: Psychoneuroendocrinology
• 影响因子: 3.7
• 作者: Dong H;Keegan JM;Hong E;Gallardo C;Montalvo-Ortiz J;Wang B;Rice KC;Csernansky J
• 通讯作者: Csernansky J

Comparisons of neuroinflammation, microglial activation, and degeneration of the locus coeruleus-norepinephrine system in APP/PS1 and aging mice.

APP/PS1 和衰老小鼠的神经炎症、小胶质细胞激活和蓝斑-去甲肾上腺素系统变性的比较。

• DOI: 10.1186/s12974-020-02054-2
• 发表时间: 2021-01-06
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Cao S;Fisher DW;Rodriguez G;Yu T;Dong H
• 通讯作者: Dong H