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

• 批准号: 9979195
• 负责人: Roberta Marongiu
• 金额: $ 21.19万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-16 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979195
• 关键词: 3-Dimensional; Abeta synthesis; Address; Age; Age-Years; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer' s disease therapy; Amyloid; Amyloid Beta A4 Precursor Protein; Amyloid beta-Protein; Angiotensin II; Animals; Area; Astrocytes; Behavioral; Biological; Brain; Brain Pathology; Brain region; Chronic; Clinical; Clinical Data; Clinical Trials; Cognitive; Cognitive deficits; Cyclohexanes; Data; Dementia; Development; Disease; Disease Progression; Enzyme-Linked Immunosorbent Assay; Estrogen Receptors; Estrogen Replacement Therapy; Estrogens; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Female; Functional disorder; Gene Delivery; Gene Expression; Genetic Transcription; Genomics; Gliosis; Goals; Hippocampus (Brain); Hormonal; Human; Human Characteristics; Hypertension; Image; Immunoassay; Immunohistochemistry; Impaired cognition; In Situ Hybridization; Inflammation; J20 mouse; Learning; Magnetic Resonance Imaging; Measures; Memory; Menopause; Messenger RNA; Metabolism; Microglia; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Nerve Degeneration; Neuroendocrinology; Neurofibrillary Tangles; Neuroglia; Neurologic; Neurons; Onset of illness; Outcomes Research; Ovariectomy; Pathogenesis; Pathologic; Pathology; Pathway interactions; Perimenopause; Periodicity; Phase; Phase Transition; Phenotype; Positron-Emission Tomography; Postmenopause; Predisposition; Prefrontal Cortex; Premenopause; Prevalence; Process; Publishing; Reporting; Research; Research Personnel; Ribosomes; Rodent Model; Senile Plaques; Sex Differences; Signal Pathway; Signal Transduction; Symptoms; Synapses; Synapsins; Testing; Therapeutic; Time; Transgenes; Vertebral column; Woman; Work; abeta accumulation; abeta deposition; adeno-associated viral vector; brain volume; cognitive development; density; differential expression; early onset; insight; male; men; mouse model; multidisciplinary; neuron loss; neuropathology; neurotransmission; new therapeutic target; novel; ovarian failure; precision medicine; prevent; promoter; public health relevance; recruit; ribosome profiling; senescence; sex; sexual dimorphism; therapeutic target

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 绝经后老年痴呆症的患病率和进展率高2-3倍 女性尊重年龄相仿的男性。除了已知的脆弱性，分子机制 导致女性阿尔茨海默病风险增加的潜在因素在很大程度上是未知的。老年痴呆症 长的前驱期，其与女性的绝经过渡期一致（围绝经期，年龄 ~45-54岁）。围绝经期妇女表现出更高水平的阿尔茨海默病脑病理 [淀粉样蛋白B（Ab）斑块、神经纤维缠结、突触丢失和慢性炎症]与 绝经前的女性和男性。这表明更年期特有的机制增加了 对阿尔茨海默病的易感性导致疾病的更早发作和更快进展。 本提案的目的是阐明围绝经期对阿尔茨海默病病理学的影响 和认知能力下降，以及确定在脑- 绝经期女性与年轻女性、男性和卵巢切除女性相比（平均 与以前发表的研究比较）。我们假设不规则的雌激素周期和雌激素- 在围绝经期雌激素受体的相互作用，而不仅仅是雌激素的损失， 更年期，通过放大脆弱大脑中的病理学来增加对阿尔茨海默氏症的易感性 导致认知缺陷更快发展的区域。我们将使用一种新的小鼠模型， 加速性卵巢衰竭（AOF），它独特地概括了人类绝经期，包括绝经后和绝经后。 绝经后（分别为绝经后和AOF后）。两个具体的目标将测试这一假设在 阿尔茨海默病的hAPP-J20（J20）小鼠模型。目的1将检验不规则雌激素 AOF周围的波动将加速认知缺陷、突触丢失和小胶质细胞的募集， 星形胶质细胞在海马和前额叶皮质（PFC）的J20小鼠相比，对照组小鼠。目标2将 测试次假设，即围AOF破坏参与Ab代谢的神经元通路，导致 与年龄相比，我们的AD女性的海马和PFC中Ab斑块的沉积增加- 匹配的控制。我们将使用先进的成像和基因组分析的独特组合 包括iDisco，它将允许全脑Ab和神经胶质激活的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mRNA库进行测序。 我们的研究结果将提供新的见解围绝经期的影响，分子 阿尔茨海默病发病机制的核心。我们的研究结果将解决NIA的战略目标： 了解阿尔茨海默氏症的进展（A），并确定潜在的治疗目标， 为男性和女性开发精确的医学治疗（D）。