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Peri-menopause as a neurological transition state that triggers Alzheimer's disease onset and accelerates disease progression

围绝经期是一种神经过渡状态，可引发阿尔茨海默病发作并加速疾病进展

基本信息

批准号：
10461352
负责人：
Roberta Marongiu
金额：
$ 8.32万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-16 至 2023-08-31
项目状态：
已结题

项目摘要

ABSTRACT Prevalence and rate of progression of Alzheimer’s disease are 2-3-fold higher in post-menopausal women respect to age-matched men. Aside from the established vulnerability, the molecular mechanisms underlying the increased risk of Alzheimer’s disease in women are largely unknown. Alzheimer’s has a long prodromal phase which coincides with the menopause transition in women (peri-menopause, age ~45-54 years). Peri-menopausal women show higher levels of Alzheimer’s disease brain pathology [amyloid b (Ab) plaques, neurofibrillary tangles, synaptic loss, and chronic inflammation] compared to pre-menopausal women and men. This suggests that mechanisms unique to peri-menopause increase the susceptibility to Alzheimer’s disease leading to earlier onset and faster progression of the disease. The goal of this proposal is to elucidate the effects of peri-menopause on Alzheimer’s disease pathology and cognitive decline, as well as to identify molecular pathways differentially expressed in peri- menopausal females compared to young females, males, and ovariectomized females (as a mean of comparison to previous published studies). We hypothesize that irregular estrogen cyclicity and estrogen- estrogen receptor interactions during peri-menopause, rather than only loss of estrogen during post- menopause, increase the susceptibility to Alzheimer’s by magnifying the pathology in vulnerable brain regions leading to faster development of cognitive deficits. We will use a novel mouse model of accelerated ovarian failure (AOF) which uniquely recapitulates human menopause including peri- and post-menopause (peri- and post-AOF respectively). Two specific aims will test this hypothesis in the hAPP-J20 (J20) mouse model of Alzheimer’s. Aim 1 will test the sub-hypothesis that irregular estrogen fluctuations at peri-AOF will accelerate cognitive deficits, synaptic loss, and recruitment of microglia and astrocytes in hippocampus and prefrontal cortex (PFC) of J20 mice compared to control mice. Aim 2 will test the sub-hypothesis that peri-AOF disrupts neuronal pathways involved in Ab metabolism resulting in increased deposition of Ab plaques in the hippocampus and PFC of our AD females compared to age- matched controls. We will use a unique combination of sophisticated imaging and genomic analysis including iDisco, which will allow the 3D quantification of whole brain Ab and glia activation, and translational ribosomal profiling (TRAP) for sequencing the pool of actively transcribed mRNA in neurons. Our research outcomes will provide novel insights into the influence of peri-menopause on molecular mechanisms central to Alzheimer’s disease pathogenesis. Our findings will address NIA strategic goals: understand the progression of Alzheimer’s (A), and identify potential therapeutic targets for the development of precision medicine treatments for men and women (D).

摘要绝经后阿尔茨海默病的患病率和进展率高出2-3倍女性尊重年龄相仿的男性。除了已确定的脆弱性外，分子机制女性患阿尔茨海默氏症风险增加的原因在很大程度上是未知的。阿尔茨海默氏症与女性的更年期(围绝经期、年龄)相一致的长前驱期 ~45-54岁)。围绝经期妇女表现出更高的阿尔茨海默病脑病理水平 [淀粉样蛋白b(Ab)斑块、神经原纤维缠结、突触丢失和慢性炎症]与绝经前的女性和男性。这表明，围绝经期特有的机制增加对阿尔茨海默氏症的易感性导致该病发病更早，进展更快。这项建议的目的是阐明围绝经期对阿尔茨海默病病理的影响和认知功能下降，以及确定在围产期差异表达的分子途径。更年期女性与年轻女性、男性和卵巢切除女性的比较(作为一种手段与以前发表的研究相比)。我们假设不规则的雌激素周期性和雌激素- 雌激素受体在围绝经期的相互作用，而不仅仅是雌激素在更年期后的丢失更年期，通过放大脆弱大脑的病理来增加阿尔茨海默氏症的易感性导致认知缺陷发展较快的地区。我们将使用一种新的小鼠模型加速性卵巢衰竭(AOF)是包括围绝经期和围绝经期在内的人类绝经期的独特表现绝经后(分别为围绝经期和绝经后)。两个具体的目标将在 HAPP-J20(J20)小鼠阿尔茨海默病模型。目的1将检验不规则雌激素 AOF周围的波动将加速认知障碍、突触丢失和小胶质细胞和 J20小鼠海马区和前额叶皮质星形胶质细胞与对照组比较。目标2将测试AOF周围干扰参与抗体代谢的神经元通路从而导致与年龄相比，AD女性海马区和PFC区抗体斑块的沉积增加。配对的对照组。我们将使用先进的成像和基因组分析的独特组合包括iDisco，它将允许对全脑抗体和胶质细胞激活进行3D量化，以及翻译核糖体分析(TRAP)用于对神经元中活跃转录的信使核糖核酸进行测序。我们的研究成果将为围绝经期对分子水平的影响提供新的见解阿尔茨海默病发病机制的核心。我们的发现将解决NIA的战略目标：了解阿尔茨海默氏症(A)的进展，并确定潜在的治疗靶点男性和女性精准医学治疗的发展(D)。