Glycolysis and Alzheimer’s Disease

糖酵解和阿尔茨海默病

• 批准号: 10516234
• 负责人: Qiang Zhang
• 金额: $ 15.45万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10516234
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Alzheimer' s disease risk; American; Amyloid; Amyloid beta-Protein; Animal Model; Automobile Driving; Autopsy; Binding; Biochemistry; Biogenesis; Biological Assay; Biology; Blood; Brain; Caloric Restriction; Clinical Trials; Data; Databases; Diabetes Mellitus; Disease; Enzyme-Linked Immunosorbent Assay; Exercise; Future; Generations; Glycolysis; Goals; Healthcare; Human; Image; Immunohistochemistry; Impaired cognition; Impairment; Intervention; Magnetic Resonance Spectroscopy; Measures; Medicare; Medicare claim; Metabolic Diseases; Metabolism; Mitochondria; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Obesity; Oral; Parkinson Disease; Pathology; Patients; Pharmaceutical Preparations; Phosphoglycerate Kinase; Physiology; Pre-Clinical Model; Process; Risk; Risk Factors; Rodent; Rodent Model; Short-Term Memory; Techniques; Testing; Transgenic Organisms; Western Blotting; Work; amyloid pathology; antagonist; base; brain dysfunction; cognitive function; effective therapy; epidemiology study; fluorodeoxyglucose positron emission tomography; glucose metabolism; improved; in vivo; in vivo magnetic resonance spectroscopy; metabolomics; mouse model; multidisciplinary; neuroimaging; neuron loss; novel; object recognition; preclinical study; prevent; protein aggregation; tamsulosin; tau Proteins; tau aggregation; terazosine

Project Summary Alzheimer's disease (AD) is a devastating disease with no disease-modifying therapies. A key contributing factor to AD is impaired glucose metabolism. However, it is unknown how glucose metabolism contributes to neurodegeneration in AD. Our recent work demonstrated that we could enhance glycolysis via an existing drug, terazosin (TZ). This drug is an alpha-1 antagonist, but it also binds to and enhances activity of phosphoglycerate kinase-1 (PGK1), the first ATP-generating step of glycolysis. Excitingly, our preliminary data from the Truven database of Medicare claims suggest that patients taking TZ are protected from developing AD relative to those taking tamsulosin, another alpha-1 antagonist that does not bind PGK1. Additionally, our review of the Alzheimer's Disease Neuroimaging initiative (ADNI) indicates that patients taking TZ have slower progression on FDG-PET and on cognitive impairment, compared to those taking tamsulosin. In this proposal, our goal is to test TZ target engagement and efficacy in animal models of AD. To our knowledge, no drug for AD directly engages PGK1 or metabolism and mitigates protein aggregation; thus, this mechanism is entirely novel for AD. Our overall hypothesis is that TZ is protective in rodent models of AD. In Aim 1, we will quantify TZ target engagement in rodent AD models. We will administer TZ orally for six-months to transgenic tau (P301S) and amyloid (5XFAD) mice relevant for human AD, along with littermate and vehicle controls. We will evaluate blood and brain metabolomics and [ATP], as well as in vivo magnetic resonance spectroscopy (MRS). In Aim 2, we will evaluate whether improving glycolysis mitigate neurodegeneration in rodent AD models. We will use the same mice as in Aim 1 and evaluate cognitive function via novel-object recognition, spatial working memory, and interval timing assays. We will also perform immunohistochemistry, ELISA, and western blot to assess tau/amyloid pathology. These studies will elucidate the basic principles of how TZ enhances brain energetics, and affects neurodegeneration. These fundamental mechanisms could be highly relevant for inspiring novel disease-modifying therapies in AD and related dementias.

项目概要 阿尔茨海默氏病 (AD) 是一种毁灭性疾病，目前尚无缓解疾病的疗法。一把钥匙 AD 的促成因素是葡萄糖代谢受损。但目前尚不清楚葡萄糖如何 新陈代谢会导致 AD 中的神经变性。我们最近的工作表明我们可以 通过现有药物特拉唑嗪 (TZ) 增强糖酵解。该药是一种 α-1 拮抗剂，但它也 结合并增强磷酸甘油酸激酶 1 (PGK1) 的活性，这是 ATP 生成的第一个步骤 糖酵解。令人兴奋的是，我们从 Truven 医疗保险索赔数据库中获得的初步数据表明： 与服用另一种药物坦索罗辛的患者相比，服用 TZ 的患者可以避免患 AD 不结合 PGK1 的 alpha-1 拮抗剂。此外，我们对阿尔茨海默病的回顾 神经影像倡议 (ADNI) 表明服用 TZ 的患者在 FDG-PET 上进展较慢 以及与服用坦索罗辛的患者相比，认知障碍的情况。在这个提案中，我们的目标是测试 TZ 目标在 AD 动物模型中的参与和功效。据我们所知，目前尚无直接治疗 AD 的药物 参与 PGK1 或新陈代谢并减轻蛋白质聚集；因此，这个机制完全是 AD小说。我们的总体假设是 TZ 在 AD 啮齿动物模型中具有保护作用。在目标 1 中，我们将 量化啮齿动物 AD 模型中的 TZ 目标参与度。我们将口服 TZ 六个月，以 与人类 AD 相关的转基因 tau (P301S) 和淀粉样蛋白 (5XFAD) 小鼠，以及同窝小鼠和 车辆控制。我们将评估血液和大脑代谢组学和 [ATP]，以及体内磁性 共振光谱（MRS）。在目标 2 中，我们将评估改善糖酵解是否可以减轻 啮齿动物 AD 模型中的神经退行性变。我们将使用与目标 1 相同的小鼠并评估 通过新奇物体识别、空间工作记忆和间隔计时分析来实现认知功能。我们 还将进行免疫组织化学、ELISA 和蛋白质印迹来评估 tau/淀粉样蛋白病理学。 这些研究将阐明 TZ 如何增强大脑能量并影响大脑的基本原理 神经变性。这些基本机制可能与启发小说高度相关 AD 和相关痴呆症的疾病缓解疗法。