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).

抽象的 绝经后，阿尔茨海默氏病的患病率和进展率高2-3倍 妇女尊重年龄匹配的男人。除了既定的脆弱性，分子机制 在女性中，阿尔茨海默氏病的风险增加的根本尚不清楚。阿尔茨海默氏症有一个 长期前阶段与女性更年期过渡一致（年份，年龄 〜45-54岁）。绝经期妇女表现出更高水平的阿尔茨海默氏病脑病理学 [淀粉样蛋白B（AB）斑块，神经原纤维缠结，突触损失和慢性感染]与 绝经前的男女。这表明机制是新生周期的特有的 阿尔茨海默氏病的敏感性导致疾病的早期发作和更快的进展。 该提议的目的是阐明培育期对阿尔茨海默氏病病理学的影响 和认知能力下降，以及鉴定分子途径在周期不同表达的分子途径 与年轻的女性，雄性和卵巢切除的女性相比，更年期女性（作为平均值 与先前发表的研究比较）。我们假设不规则的雌激素环节性和雌激素 - 雌激素受体相互作用期间，而不仅仅是雌激素的损失 更年期，通过放大脆弱大脑的病理来增加对阿尔茨海默氏症的敏感性 导致认知缺陷的更快发展的区域。我们将使用一种新颖的鼠标模型 加速卵巢衰竭（AOF），它独特地概括了包括周期和包括骨的更年期 年份后（分别为AOF和AOF）。两个具体目标将在 Happ-J20（J20）老鼠的鼠标模型。 AIM 1将测试不规则雌激素的亚物种 骨周围的波动将加速认知缺陷，突触损失以及小胶质细胞的募集和募集 与对照小鼠相比，J20小鼠的海马和前额叶皮层（PFC）中的星形胶质细胞（PFC）。 AIM 2意志 测试亚称的亚螺旋中的痛苦破坏与AB代谢有关的神经元途径，从而导致 与年龄相比 匹配的控件。我们将使用复杂成像和基因组分析的独特组合 包括IDISCO，这将允许对整个大脑AB和神经胶质激活的3D定量，以及 用于测序神经元中主动转录的mRNA池的翻译核糖体分析（陷阱）。 我们的研究成果将提供有关培育期对分子影响的新见解 机制是阿尔茨海默氏病发病机理的中心。我们的发现将解决NIA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 开发男性和女性的精确医学治疗方法（D）。