Cell autonomous mechanisms of Apolipoprotein E isoform-dependent neurodegeneration

载脂蛋白E异构体依赖性神经变性的细胞自主机制

• 批准号: 9121316
• 负责人: Anil R Wadhwani
• 金额: $ 4.86万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9121316
• 关键词: Affect; Age; Alleles; Alzheimer' s Disease; Amyloid; Apolipoprotein E; Applications Grants; Area; Astrocytes; Binding; Brain; Buffers; Calcium; Calcium-Binding Proteins; Caring; Cell Death; Cell model; Cells; Clinical; Clinical Research; Complex; Data; Dementia; Development; Disease; Early Diagnosis; Functional disorder; Genes; Genetic; Genetic Risk; Genotype; Glutamates; Health; Heterozygote; Homeostasis; Human; Image; Impaired cognition; Inherited; Investigation; Ionophores; Laboratories; Learning; Memory; Memory impairment; Molecular; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Pathway interactions; Patients; Phenotype; Population; Predisposition; Process; Protein Isoforms; Research; Risk; Risk Factors; Rodent; Role; Stem cells; Stress; Synapses; Syndrome; Testing; Toxic effect; Training; Transgenic Mice; aged; amyloid peptide; amyloid precursor protein processing; basal forebrain cholinergic neurons; base; brain cell; career; cell type; cerebral atrophy; cholinergic neuron; disorder control; excitotoxicity; gene product; genetic risk factor; induced pluripotent stem cell; insight; molecular dynamics; neuron loss; novel; prevent; response; stem cell biology; stressor; successful intervention; tau Proteins

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.

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，临床特征为早期学习和记忆缺陷，进展为严重的和迄今不可逆的痴呆。绝大多数病例是零星发生的，年龄和遗传是发病的最大风险因素。APOE基因与散发性AD的发生和临床进展最密切相关。APOE的分子动力学是复杂的，这是由于等位基因同种型的差异效应以及多种细胞类型的合成和分泌。为了解开这一复杂性，我们的实验室已经从散发性AD患者中产生了诱导多能干细胞。虽然大脑中的大多数APOE是由星形胶质细胞产生的，但我们实验室以前的研究结果表明，APOE基因型与人类基底前脑胆碱能神经元中的AD相关表型相关-这是一种在AD早期死亡的细胞群。关于神经元APOE在神经退行性变化中的作用，信息有限。因此，该提议将检验以下假设：APOE亚型在胆碱能神经元中发挥细胞自主作用，导致淀粉样蛋白加工（Aim 1）和钙稳态（Aim 2）改变。我们在散发性AD遗传风险的这种新型人类细胞模型中的发现将建立在以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基因亚型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种作用，并确定与AD分子机制的关键交叉点。在这样做的过程中，我们的目标是制定早期诊断和更成功地干预这种使人衰弱的疾病的战略。