Glycolysis and Alzheimer’s Disease

项目摘要 阿尔茨海默病(AD)是一种毁灭性的疾病，没有改变疾病的治疗方法。一把钥匙 导致阿尔茨海默病的因素是糖代谢受损。然而，目前尚不清楚葡萄糖是如何 代谢参与阿尔茨海默病的神经退行性变。我们最近的研究表明，我们可以 通过现有的药物特拉唑嗪(TZ)增强糖酵解。这种药物是一种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生成的第一步 糖酵解。令人兴奋的是，我们来自Truven医疗保险索赔数据库的初步数据表明 与服用坦索罗辛的患者相比，服用TZ的患者不会患上阿尔茨海默病。 不结合PGK1的α-1拮抗剂。此外，我们对阿尔茨海默氏症的回顾 神经成像主动性(ADNI)表明服用TZ的患者FDG-PET进展较慢 与服用坦索罗辛的人相比，在认知障碍方面也是如此。在这个提案中，我们的目标是测试 阿尔茨海默病动物模型中TZ靶点的介入和疗效。据我们所知，没有直接治疗AD的药物 参与PGK1或代谢，减轻蛋白质聚集；因此，这一机制完全是 为AD写的小说。我们的总体假设是，TZ对AD的啮齿动物模型具有保护作用。在目标1中，我们将 在啮齿动物AD模型中量化TZ目标参与度。我们将口服TZ六个月，以 与人类阿尔茨海默病相关的转基因tau(P301S)和淀粉样蛋白(5XFAD)小鼠，以及窝鼠和 车辆控制系统。我们将评估血液和大脑代谢组学和[ATP]，以及体内磁性 共振光谱学(MRS)。在目标2中，我们将评估改善糖酵解是否可以缓解 啮齿动物AD模型中的神经变性。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时间分析的认知功能。我们 还将进行免疫组织化学、酶联免疫吸附试验和免疫印迹以评估tau/淀粉样蛋白的病理。 这些研究将阐明TZ增强大脑能量的基本原理，并影响 神经退行性变。这些基本机制可能与鼓舞人心的小说高度相关 阿尔茨海默病和相关痴呆症的疾病修正疗法。

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.