Aging and hyperglycemia alter molecular mechanisms and hippocampal oscillations consistent with Alzheimer's disease

项目摘要/摘要 阿尔茨海默病(AD)是一种以进行性丧失为特征的神经退行性疾病 对记忆的记忆。AD的病理特征包括淀粉样β蛋白(Aβ)斑块沉积， 神经纤维缠结(NFT)的形成和突触和神经元的进行性丧失。一个 越来越多的文献表明，大脑中的免疫激活，特别是激活 小胶质细胞通过促进Aβ沉积和NFT参与AD的发生和发展。 目前尚不清楚阿尔茨海默病的病因，然而，已在 AD的发展，包括糖尿病(DM)和高龄。糖尿病患者有 患阿尔茨海默病的风险增加1.5-4倍。DM通过精确的机制来增加 AD的风险尚不清楚，但DM与免疫激活有关。因为DM更普遍 在老年人群中，这两个危险因素很可能在AD的发病机制中相结合。我们 假设糖尿病患者的炎症活性升高，并随着年龄的增加而加剧 由于炎症加剧了AD的病理，导致AD风险增加的主要驱动因素。各别 数据表明，内源性神经递质GABA能够调节 小胶质细胞和免疫功能，并可能对糖尿病患者的AD风险起到治疗作用， 以及合并糖尿病的AD患者。在初步调查中，我们已经证明 已获FDA批准的GABA受体激动剂在糖尿病动物模型中的应用 挽救学习和记忆缺陷、tau磷酸化(NFT)和免疫激活 符合AD临床人群和AD动物模型系统。 提出的这项研究将提供一个机会来确定升高的炎症 在男性和女性中，与糖尿病相关的疾病是AD病理的主要因素。此外， 建议的实验将在我们的初步数据的基础上扩展，以包括对网络的评估 AD中的功能中断，以及确定救援是否通过直接调节 小胶质细胞。最后，来自拟议研究的数据将阐明潜在的机制 抢救AD相关病理，并提供必要的数据支持重新定位 FDA已经批准的一种药物，可用于AD人群的一大部分。

Project Summary/Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive loss of memory. Pathological hallmarks of AD include amyloid-beta (Aβ) plaque deposition, neurofibrillary tangle (NFT) formation and the progressive loss of synapses and neurons. A growing literature has demonstrated immune activation in the brain, in particular activated microglia contribute to the onset and progression of AD by facilitating Aβ deposition and NFTs. There is no known cause for AD, however, several risk factors have been identified in the development of AD, including diabetes mellitus (DM) and advanced age. Patients with DM have a 1.5-4 fold increased risk of developing AD. The precise mechanisms by which DM increases the risk of AD is not known, but DM is associated with immune activation. As DM is more prevalent in aging populations it is likely these 2 risk factors combine in the pathogenesis of AD. We hypothesize that elevated inflammatory activation in DM, that is exacerbated by age is the primary driver of increased risk for AD, given inflammation exacerbates AD pathology. Separate data indicate the endogenous neurotransmitter GABA is capable of modulating activation of microglia and immune function and could serve a therapeutic role in DM patients at risk for AD, as well as AD patients comorbid with DM. In preliminary investigations we have demonstrated administration of an already FDA approved GABA receptor agonist in a DM animal model rescues learning and memory deficits, tau phosphorylation (NFT), and immune activation consistent with AD clinical populations and AD animal model systems. The research proposed will provide an opportunity to determine if the elevated inflammation associated with DM is a major contributor to AD pathology, in both males and females. Further, the experiments proposed will expand on our preliminary data to include evaluation of network function disrupted in AD, as well as determine if the rescue is mediated via direct modulation of microglia. Lastly, the data from the proposed research will elucidate the mechanisms underlying the rescue of AD related pathology and provide the necessary data to support the repurposing of an already FDA approved drug for use in a large subset of the AD population.