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

衰老和高血糖改变了与阿尔茨海默病一致的分子机制和海马振荡

• 批准号: 9884190
• 负责人: James M. Hyman
• 金额: $ 60.38万
• 依托单位: UNIVERSITY OF NEVADA LAS VEGAS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884190
• 关键词: Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Disease Models; Animal Model; Animals; Area; Baclofen; Behavioral; Biological Models; Brain; Cell Survival; Cells; Clinical; Data; Deposition; Development; Diabetes Mellitus; Disease Progression; Dose; Drug usage; Elderly; Evaluation; Exhibits; FDA approved; Female; GABA Agonists; General Population; Hippocampus (Brain); Hyperglycemia; Immune response; Impaired cognition; Individual; Inflammation; Inflammatory; Inflammatory Response; Insulin Receptor; Investigation; Laboratories; Learning; Literature; Measures; Mediating; Memory; Memory Loss; Memory impairment; Microglia; Modeling; Molecular; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neurotransmitters; Onset of illness; Pancreas; Pathogenesis; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Population; Prediabetes syndrome; Prefrontal Cortex; Receptor Signaling; Research; Resistance; Risk; Risk Factors; Rodent; Role; Senile Plaques; Sex Differences; Signal Transduction; Streptozocin; Structure of beta Cell of islet; Synapses; TREM2 gene; Therapeutic; Time; Transgenic Mice; abeta deposition; aged; apolipoprotein E-4; comorbidity; cytokine; diabetogenic; experimental study; functional decline; gamma-Aminobutyric Acid; hyperphosphorylated tau; immune activation; immune function; insight; male; neurofibrillary tangle formation; neuroinflammation; novel; progressive neurodegeneration; receptor; tau phosphorylation; therapeutic development

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.

项目概要/摘要 阿尔茨海默氏病 (AD) 是一种神经退行性疾病，其特征是进行性丧失 AD 的病理特征包括淀粉样蛋白 (Aβ) 斑块沉积、 神经原纤维缠结 (NFT) 的形成以及突触和神经元的逐渐丧失 A。 越来越多的文献证明大脑中的免疫激活，特别是激活的 小胶质细胞通过促进 Aβ 沉积和 NFT 促进 AD 的发生和进展。 AD 的病因尚不清楚，但是，已在 AD 中发现了几个危险因素 AD 的发展，包括糖尿病 (DM) 和高龄 DM 患者。 患 AD 的风险增加 1.5-4 倍 DM 增加的确切机制。 AD 的风险尚不清楚，但 DM 与免疫激活有关，因为 DM 更为普遍。 在老龄化人群中，这两种危险因素很可能共同导致 AD 的发病机制。 DM 中的炎症激活升高，并且随着年龄的增长而加剧，这是 鉴于炎症会加剧 AD 病理，这是 AD 风险增加的主要驱动因素。 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，可以对有 AD 风险的 DM 患者起到治疗作用， 以及患有 DM 的 AD 患者。在初步调查中我们已经证明。 在 DM 动物模型中使用 FDA 批准的 GABA 受体激动剂 挽救学习和记忆缺陷、tau 蛋白磷酸化 (NFT) 和免疫激活 与AD临床人群和AD动物模型系统一致。 拟议的研究将提供一个机会来确定炎症是否升高 与 DM 相关的疾病是导致男性和女性 AD 病理的主要因素。 拟议的实验将扩展我们的初步数据，包括网络评估 AD 中的功能中断，以及确定救援是否是通过直接调节来介导的 最后，拟议研究的数据将阐明其潜在机制。 挽救 AD 相关病理并提供必要的数据以支持重新利用 一种 FDA 已批准用于大部分 AD 人群的药物。