The role of sex in GABAergic-mediated, Alzheimer’s disease-related episodic memory impairments from mid to late life

性在 GABA 能介导的、阿尔茨海默病相关的中晚年情景记忆障碍中的作用

• 批准号: 10693240
• 负责人: Teal S Eich
• 金额: $ 81.09万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693240
• 关键词: Accounting; Affect; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; American; Amyloid beta-Protein; Animal Experimentation; Animals; Apolipoproteins; Area; Behavioral; Biological Assay; Brain; Brain imaging; Clinical; Clinical Trials; Cognitive; Communities; Dementia; Development; Diagnosis; Disparity; Elderly; Episodic memory; Estradiol; Estrogen decline; Estrogens; Event; Female; Functional disorder; Genetic Risk; Gonadal Steroid Hormones; Hippocampus; Hormones; Human; Hyperactivity; Impaired cognition; Impairment; Individual; Individual Differences; Inhibitory Synapse; Interneurons; Intervention; Longevity; Mediating; Memory; Memory Loss; Memory impairment; Menopause; Modeling; Morphology; Neurobehavioral Manifestations; Neurobiology; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathology; Pattern; Perimenopause; Play; Positron-Emission Tomography; Postmenopause; Premenopause; Progesterone; Quality of life; Risk; Role; Sampling; Sex Differences; Symptoms; System; Techniques; Testing; Woman; Work; abeta accumulation; age related; apolipoprotein E-4; episodic memory impairment; gamma-Aminobutyric Acid; genetic risk factor; hippocampal pyramidal neuron; human female; human male; human model; improved; male; memory consolidation; men; middle age; neural model; neurotoxicity; new therapeutic target; precision medicine; receptor; sex; steroid hormone; symposium; theories

Project Summary Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that severely hinders quality of life. It is the leading cause of dementia in the elderly, and disproportionately affects women. Not only are women more likely to be diagnosed with AD, but when they are, they show steeper rates of episodic memory decline, the hallmark clinical symptom of AD. Studies using animals have provided strong evidence that γ-aminobutyric acid (GABA) plays a critical role in episodic memory by regulating neuronal activity in the hippocampus –a brain area that undergoes morphologic and functional changes in aging and AD. Experimentally induced estrogen depletion, again in studies in animals, results in reductions in GABA. Furthermore, it has been shown that apolipoprotein ε4 –the strongest common genetic risk factor for AD– is particularly detrimental in females, and exacerbates dysfunction of the GABAergic system. This proposal extends these findings to test a sex- specific, biologically-based GABAergic model of neural and episodic memory impairments in humans. By capitalizing upon recent technical advancements in brain imaging and sex steroid hormone assay techniques, this project will directly test whether hippocampal GABA concentration impacts brain activity and episodic memory in a community-dwelling sample of middle-aged and older adults at risk for developing AD. Further, this project will be the first of its kind to focus on the consequences of the decreases in estrogen accompanying menopause in human females for the GABAergic cascade. The results of this project will have important implications for our understanding of the neurobiological basis of AD and its cognitive symptoms, and may, in turn, spark new therapeutic targets of intervention.

项目概要 阿尔茨海默病（AD）是一种进行性神经退行性疾病，严重影响生活质量。这是 这是导致老年人痴呆的主要原因，并且对女性的影响尤为严重。不仅女性更 很可能被诊断出患有 AD，但当他们被诊断出患有 AD 时，他们的情景记忆衰退速度更快， AD 的标志性临床症状。使用动物进行的研究提供了强有力的证据表明γ-氨基丁酸 氨基丁酸 (GABA) 通过调节海马体的神经元活动在情景记忆中发挥着关键作用 –a 在衰老和 AD 过程中经历形态和功能变化的大脑区域。实验诱导 在动物研究中，雌激素消耗也会导致 GABA 减少。此外，还显示 载脂蛋白ε4——AD最常见的遗传风险因素——对女性尤其有害， 并加剧 GABA 能系统的功能障碍。该提案将这些发现扩展到测试性别 人类神经和情景记忆损伤的特定的、基于生物学的 GABAergic 模型。经过 利用脑成像和性类固醇激素测定技术的最新技术进步， 该项目将直接测试海马 GABA 浓度是否影响大脑活动和情景 社区居民样本中存在 AD 风险的中老年人的记忆力。更远， 该项目将是同类项目中第一个关注雌激素减少的后果的项目 伴随人类女性更年期的 GABA 级联反应。该项目的成果将有 对我们理解 AD 的神经生物学基础及其认知症状具有重要意义， 反过来，可能会引发新的干预治疗目标。