Cell autonomous mechanisms of Apolipoprotein E isoform-dependent neurodegeneration

描述(由申请人提供)：阿尔茨海默病是一种复杂的多因素综合征，临床特征是早期学习和记忆障碍，发展为严重的迄今不可逆转的痴呆症。绝大多数病例是零星发生的，年龄和遗传是发病的最大危险因素。APOE基因与散发性AD的发生和临床进展密切相关。由于不同细胞类型的等位基因异构体和合成分泌的不同作用，APOE的分子动力学是复杂的。为了揭开这种复杂性，我们的实验室从散发性阿尔茨海默病患者中培养出了诱导多能干细胞。虽然大脑中的大部分APOE是由星形胶质细胞产生的，但我们实验室之前的发现表明，APOE基因与人类基底前脑胆碱能神经元中与AD相关的表型有关--这是一个在AD早期死亡的细胞群体。关于神经元载脂蛋白E在神经退行性改变中的作用，可获得的信息有限。因此，这项提议将检验APOE亚型在胆碱能神经元中发挥细胞自主效应，导致淀粉样蛋白加工改变(目标1)和钙稳态(目标2)的假设。我们在这一新的散发性阿尔茨海默病遗传风险人类细胞模型中的发现将建立在先前啮齿动物和人类临床研究的基础上，同时提供前所未有的对基因亚型和细胞类型表达的实验控制。这项拟议的研究将阐明载脂蛋白E在人类神经细胞中的多种作用，并确定与拟议的AD分子机制的关键交叉点。通过这样做，我们的目标是制定策略，以便对这种使人衰弱的疾病进行更早的诊断和更成功的干预。

DESCRIPTION (provided by applicant): Alzheimer's disease is a complex, multifactorial syndrome characterized clinically by early learning and memory deficits that progress into a severe and as-of-yet irreversible dementia. The vast majority of cases occur sporadically, and age and genetics are the strongest risk factors for onset. The APOE gene is the most strongly associated with the development and clinical progression of sporadic AD. The molecular dynamics of APOE are complex due to differential effects of allelic isoform and synthesis and secretion by multiple cell types. To unravel this complexity, our laboratory has generated induced pluripotent stem cells from patients with sporadic AD. Though the majority of APOE in the brain is produced by astrocytes, previous findings from our lab demonstrated an association of APOE genotype with AD-relevant phenotypes in human basal forebrain cholinergic neurons - a cell population which dies early in AD. Limited information is available about the role of neuronal APOE in neurodegenerative change. This proposal will therefore test the hypothesis that APOE isoform exerts cell autonomous effects in cholinergic neurons that result in altered amyloid processing (Aim 1) and calcium homeostasis (Aim 2). Our findings in this novel human cellular model of genetic risk in sporadic AD will build upon insight from previous rodent and human clinical studies while providing unprecedented experimental control of gene isoform and cell type of expression. The proposed studies will clarify the multiple roles of APOE in human neural cells and identify critical intersections with proposed molecular mechanisms for AD. In doing so, we aim to develop strategies for earlier diagnosis and more successful intervention of this debilitating disease.