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; 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.

项目摘要 阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，严重阻碍了生活质量。这是 老年痴呆症的主要原因，并不成比例地影响女性。不仅女人更多 可能被诊断为AD，但是当它们显示出时，它们显示出钢铁发作的记忆率下降， AD的Hallmark临床症状。使用动物的研究提供了有力的证据表明γ-氨基幼虫 酸（GABA）通过调节海马中的神经元活性在情节记忆中起关键作用 - A 大脑区域会发生衰老和AD的形态和功能变化。实验诱导 在动物研究中，雌激素的部署再次导致GABA减少。此外，它已显示 载脂蛋白ε4（AD的强大常见遗传危险因素）在女性中尤其有害， 加剧了GABA能系统的功能障碍。该建议扩展了这些发现以测试性别 - 人类神经和情节记忆障碍的特定，基于生物学的GABA能模型。经过 利用大脑成像和性刻板印象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节 在社区居住的中年和老年人中有可能发展AD风险的记忆。更远， 该项目将是第一个专注于雌激素下降的后果的项目 参加GABA能级联的人类女性的绝经。该项目的结果将有 我们对AD神经生物学基础及其认知症状的理解的重要意义， 可能反过来又引发了新的干预措施。