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，临床表现为早期学习和记忆缺陷，并发展为严重且尚不可逆的痴呆症。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基因与散发性阿尔茨海默病的发生和临床进展密切相关。APOE的分子动力学是复杂的，因为等位基因异构体的不同影响以及多种细胞类型的合成和分泌。为了解开这种复杂性，我们的实验室从散发性阿尔茨海默病患者身上产生了诱导多能干细胞。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研究结果表明，APOE基因型与人类基底前脑胆碱能神经元（一种早死于AD的细胞群）的AD相关表型存在关联。关于神经元APOE在神经退行性改变中的作用的信息有限。因此，该提议将验证APOE亚型在胆碱能神经元中发挥细胞自主作用的假设，从而导致淀粉样蛋白加工（Aim 1）和钙稳态（Aim 2）的改变。我们在这个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以前的啮齿动物和人类临床研究的基础上，同时提供前所未有的基因异构体和细胞类型表达的实验控制。拟议的研究将阐明APOE在人类神经细胞中的多重作用，并确定AD分子机制的关键交叉点。在此过程中，我们的目标是制定早期诊断和更成功干预这种使人衰弱的疾病的策略。

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.