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: 10540130
• 负责人: Teal S Eich
• 金额: $ 81.42万
• 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/10540130
• 关键词: Accounting; Affect; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; American; Amyloid beta-Protein; Animals; Apolipoproteins; Area; Behavioral; Biological Assay; Brain; Brain imaging; Clinical; Cognitive; Communities; Dementia; Development; Diagnosis; Elderly; Episodic memory; Estradiol; Estrogens; Event; Female; Functional disorder; Genetic Risk; Gonadal Steroid Hormones; Hippocampus (Brain); 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; Play; Positron-Emission Tomography; Postmenopause; Premenopause; Progesterone; Quality of life; Risk; Role; Sampling; Sex Differences; Suggestion; Symptoms; System; Techniques; Testing; Woman; Work; abeta accumulation; age related; apolipoprotein E-4; base; 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; new therapeutic target; precision medicine; receptor; sex; spatial memory; 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 阿尔茨海默病（AD）是一种严重影响生活质量的进行性神经退行性疾病。是 是老年痴呆症的主要原因，对女性的影响尤其严重。不仅女性更 可能被诊断为AD，但当他们被诊断为AD时，他们的情景记忆下降速度更快， AD的标志性临床症状。利用动物进行的研究提供了有力的证据， 谷氨酸（GABA）通过调节海马神经元的活动在情景记忆中起着关键作用， 在衰老和AD中经历形态和功能变化的脑区。实验诱导 同样在动物研究中，雌激素耗竭导致GABA减少。此外，它已被证明 载脂蛋白ε4 --AD最常见的遗传风险因子--在女性中尤其有害， 并加重GABA能系统的功能障碍。这项建议将这些发现扩展到测试性别- 人类神经和情景记忆障碍的特异性、基于生物学的GABA能模型。通过 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浓度是否会影响大脑活动和偶发事件。 记忆在社区居住的样本中的中年和老年人在发展AD的风险。此外，本发明还 这个项目将是第一个关注雌激素减少的后果的项目。 伴随更年期的女性中GABA能级联反应。该项目的成果将 对我们理解AD及其认知症状的神经生物学基础具有重要意义， 并可能反过来引发新的干预治疗目标。