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: 10264833
• 负责人: Roberta Marongiu
• 金额: $ 25.43万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10264833
• 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).

抽象的 绝经后阿尔茨海默病的患病率和进展率高出 2-3 倍 除了既定的脆弱性之外，女性还尊重年龄相匹配的男性。 女性患阿尔茨海默氏病的风险增加的根本原因尚不清楚。 与女性更年期过渡相一致的长前驱期（围绝经期、年龄 约 45-54 岁）。 [淀粉样蛋白 b (Ab) 斑块、神经原纤维缠结、突触损失和慢性炎症] 与 这表明围绝经期特有的机制会增加。 对阿尔茨海默氏病的易感性导致该病发病较早且进展较快。 该提案的目标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，以及识别在周围环境中差异表达的分子途径 更年期女性与年轻女性、男性和切除卵巢的女性相比（作为 与之前发表的研究进行比较）。 围绝经期期间雌激素受体的相互作用，而不仅仅是绝经后雌激素的损失 更年期，通过放大脆弱大脑的病理学来增加对阿尔茨海默氏症的易感性 我们将使用一种新的小鼠模型来识别导致认知缺陷更快发展的区域。 卵巢加速衰竭（AOF）独特地概括了人类更年期，包括围绝经期和绝经期 绝经后（分别是 AOF 前后和 AOF 后）将检验这一假设。 hAPP-J20 (J20) 阿尔茨海默氏症小鼠模型将测试雌激素不规律的子假设。 AOF 周围的波动将加速认知缺陷、突触损失以及小胶质细胞和 J20 小鼠海马和前额皮质 (PFC) 中的星形胶质细胞与对照 Aim 2 小鼠相比。 测试以下子假设：peri-AOF 破坏参与 Ab 代谢的神经元通路，导致 与年龄相比，AD 女性海马体和 PFC 中抗体斑块的沉积增加 我们将使用复杂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神经胶质细胞激活进行 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 mRNA 库进行测序。 我们的研究成果将为围绝经期对分子的影响提供新的见解。 我们的研究结果将解决 NIA 的战略目标： 了解阿尔茨海默病的进展 (A)，并确定潜在的治疗靶点 开发针对男性和女性的精准医学治疗 (D)。