Sex Differences in Alzheimer's disease-Related Pathology: Role of Mitochondrial Function and Metabolic Health

项目摘要/摘要 我的职业目标是成为阿尔茨海默病性别差异研究领域的领军人物 (Ad)，特别关注代谢介体和线粒体功能。为此，我的具体训练 这份K01提案的目标包括：1)增加关于大脑性别差异的专业知识， 2)扩展与AD有关的代谢和线粒体功能方面的知识，并接受 生物标记物研究，以及3)精通翻译研究和数据分析的生物统计学。 NIA K01指导研究科学家发展奖将支持我的培训并为我提供 成为独立调查员所需的知识基础和技能。这些培训目标将是 在测试我的具体目标的同时实现的，这些目标建立在有希望的初步数据基础上 表明新陈代谢健康可能会影响绝经过渡期的记忆回路功能 通过氧化应激的机制。 三分之二的AD患者是女性。除了预期寿命外，还有性别和 与性别相关的遗传和生理因素导致女性AD的发生率较高。中年 代谢功能障碍在性别上有显著差异，长期以来一直被认为是AD的危险因素。 尽管如此，这种关系背后的病理生理学在很大程度上仍不清楚。我会测试一下的 线粒体功能在理解记忆回路性别差异中起关键作用的假说 功能与AD相关病理的早期出现。将从独特的新产品中利用数据 英国家庭研究(NEFS)产前队列(N=212；106M：106F)，出生于1959-1966年间，随后 &gt；60年。详细的病史/生育史、新陈代谢评估、记忆评估和存储 血样采集自45-55岁的后代(R01MH090291中的T1)。这些人都是 目前正在接受为期8年的跟踪评估，年龄52-65岁(R01AG067019中的T2)，使用相同的T1 使用其他脑成像方式的措施。我有一个独特的机会来研究 线粒体功能以性别依赖的方式影响记忆回路和AD相关的病理。此外， 从T1到T2，一些女性过渡到更年期，因此我将能够前瞻性地探索 生殖衰老、代谢健康和线粒体功能对记忆力下降和 阿尔茨海默病相关病理堆积。这项提案将研究线粒体作为一种 记忆回路性别差异与AD发病风险的病理生理机制。调查结果将会有 对脑部和代谢紊乱并存的重大长期影响和突出潜力 治疗策略的机械性靶点。

Project Summary/Abstract My career goal is to become a leading researcher in the field of sex differences in Alzheimer’s disease (AD), with a specific focus on metabolic mediators and mitochondrial function. To this end, my specific training goals in this K01 proposal include: 1) Increasing expertise and knowledge around sex differences in the brain, 2) Expanding my knowledge in metabolic and mitochondrial function in relation to AD and obtain training in biomarker research, and 3) Developing proficiency in translational research and biostatistics for data analysis. The NIA K01 Mentored Research Scientist Development Award will support my training and provide me with the knowledge base and skills needed to become an independent investigator. These training goals will be achieved in conjunction with the testing of my specific aims, which are built on promising preliminary data showing that metabolic health impacts memory circuitry function over the menopausal transition, potentially through mechanisms of oxidative stress. Two-thirds of patients with AD are women. Beyond life expectancy rates, there are sex-specific and sex-dependent genetic and physiologic factors that contribute to the higher frequency of AD in women. Midlife metabolic dysfunction, which significantly differs by sex, has long been recognized as a risk factor for AD. Despite this, the pathophysiology underlying this relationship remains largely unknown. I will test that hypothesis that mitochondrial function plays a critical role in understanding sex differences in memory circuitry function and the early emergence of AD-related pathology. Data will be leveraged from the unique New England Family Study (NEFS) prenatal cohort (N=212; 106M:106F), born between 1959-1966 and followed for >60 years. Detailed medical/reproductive histories, metabolic assessments, memory assessments, and stored blood samples were collected from offspring at ages 45-55 (T1 in R01MH090291). These same individuals are currently being assessed in an 8-year follow up, at ages 52-65 (T2 in R01AG067019), using the same T1 measures with additional brain imaging modalities. I have a unique window of opportunity to examine how mitochondrial function affects memory circuitry and AD-related pathology in a sex-dependent manner. Further, from T1 to T2, some women transitioned to menopause and thus I will be able to prospectively explore the longitudinal impact of reproductive aging, metabolic health, and mitochondrial function on memory decline and the accumulation of AD-related pathology. This proposal will examine mitochondrial function as a pathophysiological mechanism for sex differences in memory circuitry and risk for AD. Findings will have significant long-term implications for the co-occurrence of brain and metabolic disorders and highlight potential mechanistic targets for therapeutic strategies.