Aberrant Glycogen Modulates Cerebral Glucose Metabolism in Aging and Alzheimer's Disease

摘要： 阿尔茨海默病（AD）的发病率随着年龄的增长而增加， 这意味着患有AD的人数正在迅速增加。脑代谢的变化是 因此，有理由假设，与年龄相关的新陈代谢变化 在AD进展中的重要作用。AD大脑显示出明显的代谢障碍，研究表明， 代谢驱动导致AD发作的级联事件。启动这些代谢的机制 损伤仍然是AD研究中的关键知识缺口。我们最近发现异常的糖原 聚集体（AD-糖原）是人类和小鼠中AD的普遍特征。AD-糖原增加 与患者标本中较高的Braak分期和较低的葡萄糖水平相关。AD-糖原既 高度磷酸化和高度分支化使它们在结构上不同于正常糖原。我们 提出强有力的证据表明AD-糖原通过直接结合调节脑代谢， AMP活化蛋白激酶（AMPK）的失活，AMPK是中心碳代谢的主要调节因子。我们 将首先阐明导致体外和体内异常AD-糖原形成的分子事件（目的1）， 然后，我们将询问AD-糖原对衰老过程中脑代谢的影响（目的2）。最后我们 将评估一种新型糖原清除酶疗法对脑代谢、认知和AD的疗效 体内神经病理学（目的3）。PI组建了一个多学科的研究者团队， 互补的技能组合和最先进的、高分辨率和基于OMIC的技术，以发现潜在的 治疗选择，并可能治疗AD的发作。

Abstract: The onset of Alzheimer's disease (AD) increases in incidence with age, and an increasing aging demographic means the number of individuals suffering from AD is expanding rapidly. Changes in cerebral metabolism are hallmarks of aging therefore it is reasonable to hypothesize that age-associated change in metabolism play major roles in AD progression. AD brains show clear metabolic impairments, and studies suggest that altered metabolism drives a cascade of events leading to AD onset. The mechanisms initiating these metabolic impairments remain a critical knowledge gap in AD research. We recently discovered that aberrant glycogen aggregates (AD-glycogen) are a universal feature of AD in both human and mice. Increases in AD-glycogen correlated with higher Braak staging and lower glucose levels in patient specimens. AD-glycogen is both hyper-phosphorylated and hyper-branched making them architecturally distinct from normal glycogen. We present strong evidence showing that AD-glycogen modulate brain metabolism through direct binding and inactivation of the AMP-activated protein kinase (AMPK), a master regulator of central carbon metabolism. We will first elucidate the molecular events leading to abnormal AD-glycogen formation in vitro and in vivo (Aim 1), then we will interrogate the impact of AD-glycogen on cerebral metabolism during aging (Aim 2). Finally, we will assess the efficacy of a novel glycogen-clearing enzyme therapy on brain metabolism, cognition, and AD neuropathology in vivo (Aim 3). The PI has assembled a multi-disciplinary team of investigators with complementary skillsets and state-of-art, high resolution, and Omic-based techniques to discover potential therapeutic options and possibly treat the onset of AD.