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

项目摘要 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。它是 这是导致老年人痴呆症的主要原因，对妇女的影响不成比例。不仅是因为女性 很可能被诊断为阿尔茨海默病，但当他们被诊断出患有阿尔茨海默病时，他们表现出更陡峭的情景记忆下降速度， 阿尔茨海默病的典型临床症状。用动物进行的研究提供了强有力的证据证明γ-氨基丁酸 酸(GABA)通过调节海马神经元活动在情景记忆中发挥关键作用 在衰老和阿尔茨海默病中经历形态和功能变化的大脑区域。实验诱导 同样在动物研究中，雌激素耗尽会导致GABA的减少。此外，它已经被证明 载脂蛋白ε4是阿尔茨海默病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。这项提案扩展了这些发现，以测试性别- 人类神经和情景记忆损害的特定的、基于生物学的GABA能模型。通过 利用大脑成像和性类固醇激素检测技术的最新技术进步， 该项目将直接测试海马区GABA浓度是否影响大脑活动和发作 社区居住样本中有患阿尔茨海默病风险的中老年人的记忆。此外， 这个项目将是第一个关注雌激素减少的后果的同类项目。 伴随更年期的人类女性的GABA能级联。这个项目的成果将会有 对我们理解阿尔茨海默病的神经生物学基础及其认知症状具有重要意义 而反过来，可能会引发新的干预治疗目标。

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.