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

阿尔茨海默病相关病理学的性别差异：线粒体功能和代谢健康的作用

• 批准号: 10643340
• 负责人: Kyoko Konishi
• 金额: $ 12.85万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643340
• 关键词: 8-hydroxy-2' -deoxyguanosine; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-42; Anterior; Area; Bioenergetics; Biological Markers; Biometry; Blood specimen; Brain; Brain Diseases; Brain imaging; Cardiometabolic Disease; Cell Respiration; Cells; Cerebrum; Chronology; Data; Data Analyses; Data Collection; Estradiol; Family Study; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Genetic; Glucose; Goals; Gonadal Steroid Hormones; Grant; Health; Hippocampus; Individual; Inferior; Insulin; Knowledge; Life Expectancy; Light; Link; Lipids; Measures; Mediating; Mediator; Medical; Memory; Memory Loss; Menopausal Status; Menopause; Mentored Research Scientist Development Award; Metabolic; Metabolic Diseases; Metabolic dysfunction; Mitochondria; New England; Organelles; Oxidative Stress; Parietal Lobe; Pathology; Pathway interactions; Performance; Perimenopause; Peripheral Blood Mononuclear Cell; Persons; Physiological; Play; Positioning Attribute; Postmenopause; Prefrontal Cortex; Premenopause; Process; Production; Public Health; Reproductive History; Research; Research Personnel; Respiration; Risk Factors; Role; Sex Differences; Site; Source; Structure; Testing; Time; Training; Translational Research; United States National Institutes of Health; Woman; Work; Writing; aged; blood-based biomarker; career; cingulate cortex; clinical diagnosis; cohort; follow-up; glucose metabolism; imaging modality; in vivo; knowledge base; men; middle age; mitochondrial dysfunction; neurofilament; novel; offspring; precision medicine; prenatal; prospective; reproductive senescence; sex; skills; targeted treatment; tau Proteins; white matter

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.

项目总结/摘要 我的职业目标是成为阿尔茨海默病性别差异领域的主要研究者 (AD)，特别关注代谢介质和线粒体功能。为此，我的具体训练 该K 01提案的目标包括：1）增加有关大脑性别差异的专业知识和知识， 2)扩展我在代谢和线粒体功能与AD相关的知识，并获得以下方面的培训： 生物标志物研究，和3）发展转化研究和数据分析的生物统计学的熟练程度。 NIA K 01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 我的目标是建立在有希望的初步数据基础上的， 这表明代谢健康会影响绝经过渡期的记忆回路功能， 通过氧化应激机制。 三分之二的AD患者是女性。除了预期寿命率，还有性别特异性和 性别依赖性遗传和生理因素，导致女性AD发病率较高。中年 代谢功能障碍因性别而显著不同，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然未知。我来测试一下 假设线粒体功能在理解记忆回路的性别差异中起着关键作用 功能和AD相关病理的早期出现。数据将利用独特的新 英格兰家庭研究（NEFS）产前队列（N=212; 106例男性：106例女性），出生于1959-1966年，随访 >60年。详细的病史/生殖史、代谢评估、记忆评估，以及储存的 从45-55岁的后代（R 01 MH 090291中的T1）收集血样。这些人是 目前正在52-65岁（R 01 AG 067019中的T2）的8年随访中使用相同的T1进行评估 用其他脑成像方式进行测量。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相关病理。此外，本发明还 从T1到T2，一些妇女过渡到更年期，因此我将能够前瞻性地探索 生殖老化、代谢健康和线粒体功能对记忆衰退的纵向影响， AD相关病理的积累。这项提案将研究线粒体功能作为一个 记忆回路性别差异的病理生理机制和AD风险。调查结果将有 对脑和代谢紊乱的共同发生具有重要的长期意义，并突出了潜在的 治疗策略的机械靶点。