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

项目总结/摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种以进行性丧失为特征的神经退行性疾病， 记忆。AD的病理学标志包括淀粉样蛋白-β（Aβ）斑块沉积， 神经纤维缠结（NFT）形成以及突触和神经元的进行性损失。一 越来越多的文献已经证明了大脑中的免疫激活，特别是激活的 小胶质细胞通过促进Aβ沉积和NFT参与AD的发生和发展。 AD的病因尚不清楚，但是，在研究中已确定了几个风险因素。 AD的发展，包括糖尿病（DM）和高龄。DM患者有 患AD的风险增加1.5-4倍。DM增加胰岛素抵抗的确切机制 AD的风险尚不清楚，但DM与免疫激活有关。由于DM更普遍， 在老年人群中，这两种危险因素可能在AD的发病机制中结合联合收割机。我们 假设糖尿病炎症激活升高，随着年龄的增长而加重， AD风险增加的主要驱动因素，因为炎症会加重AD病理。单独 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，并可在有AD风险的DM患者中发挥治疗作用， 以及AD患者与DM共病。在初步调查中，我们已经证明 在DM动物模型中施用已经FDA批准的GABA受体激动剂 挽救学习和记忆缺陷，tau磷酸化（NFT）和免疫激活 与AD临床人群和AD动物模型系统一致。 这项研究将提供一个机会，以确定是否升高的炎症 在男性和女性中，与DM相关的糖尿病是AD病理学的主要贡献者。此外，本发明还 建议的实验将扩大我们的初步数据，包括评估网络 在AD中功能被破坏，以及确定是否通过直接调节 小胶质细胞最后，拟议研究的数据将阐明其背后的机制 挽救AD相关病理学，并提供必要的数据，以支持 这是一种已经被FDA批准用于大部分AD人群的药物。

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.