Understanding the molecular mechanisms of Depression and Psychological Well-being in Alzheimer's disease

了解阿尔茨海默病抑郁和心理健康的分子机制

• 批准号: 10159824
• 负责人: Aliza Pham Wingo
• 金额: $ 73万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159824
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Autopsy; Biological; Brain; Cause of Death; Cessation of life; Cognition; Cognitive; Confounding Factors (Epidemiology); DICER1 gene; Data; Data Set; Dementia; Development; Diagnostic tests; Disease; Enzymes; Gene Expression; Genes; Genetic Translation; Genetic study; Genomics; Human; Impaired cognition; Impairment; Individual; Joints; Light; Longitudinal prospective study; Memory; Mental Depression; Messenger RNA; MicroRNAs; Modeling; Molecular; Outcome; Pathology; Pathway Analysis; Post-Transcriptional Regulation; Prefrontal Cortex; Proteins; Proteome; Proteomics; Public Health; Quantitative Trait Loci; Role; Sampling; Synaptic plasticity; Testing; Transcript; Untranslated RNA; Well in self; base; clinical Diagnosis; cognitive change; differential expression; disease mechanisms study; disease phenotype; genome-wide; insight; memory consolidation; next generation sequencing; novel; novel diagnostics; physical conditioning; tau Proteins; transcriptome; transcriptomics

Psychological well-being (PWB) and depression are important factors that modify risk for Alzheimer's disease (AD), a disorder of progressive erosion of memory and cognition. Specifically, depression is associated with increased risk for AD dementia while PWB with decreased risk for AD after controlling for depression. Molecular mechanisms underlying these important associations, however, are not known and are the focus of this proposal. Based on emerging evidence from our studies and others', we hypothesize that altered expression of key microRNAs (miRNAs) contribute to the effects of depression and PWB on AD risk. To test this hypothesis we propose to study a unique dataset of 850 human postmortem brains from the Rush Memory and Aging Project (MAP). This prospective longitudinal study annually collects data on depression, PWB, cognition, physical health, and dementia, and genomic, transcriptomic, and proteomic data from the dorsolateral prefrontal cortex (dPFC). We propose a 2-stage genetic study to identify key miRNAs, transcripts, and proteins associated with depression, and separately with PWB, and examine how they relate to cognitive change, AD dementia, and dementia-related pathologies. Our discovery dataset will be the 600 MAP samples and replication set will be 250 MAP samples, followed by a joint analysis of all 850. In Aim 1 we propose to identify miRNAs specific to depression and PWB, respectively, through genome-wide miRNA expression analyses. We will then determine how these miRNAs are associated with AD phenotypes (i.e. rate of cognitive decline, clinical diagnosis of dementia, and dementia-related pathologies). We anticipate identifying miRNAs significantly associated with both depression and AD (referred to as Dep-AD- miRNAs), and to both PWB and AD (PWB-AD-miRNAs). In Aim 2, we examine transcript levels of the targets of the Dep-AD-miRNAs and PWB-AD-miRNAs in AD phenotypes. We hypothesize that mRNA levels of these targets will be associated with AD phenotypes. Additionally, we will perform co-expression network analysis on existing transcriptomes to identify expression modules and key expression drivers for depression and PWB, separately. We will then test if these key expression drivers are associated with AD phenotypes. In Aim 3, we will examine protein levels of the downstream targets of the Dep-AD-miRNAs and PWB-AD-miRNAs in AD phenotypes. We also test whether protein levels of the significant transcripts from Aim 2 are associated with AD phenotypes. Lastly, we will perform network analysis on existing global proteomes to identify novel proteomic drivers for depression and PWB, respectively, and examine their association with AD phenotypes. This project can potentially identify important molecular contributors of AD dementia that might not be apparent through other approaches, leading to new insights into mechanisms and treatment targets for AD and thereby have an important and sustained impact on public health.

心理健康（PWB）和抑郁症是改变阿尔茨海默氏症风险的重要因素 疾病（AD），一种对记忆和认知进行性侵蚀的障碍。具体来说，抑郁症是 与AD痴呆症风险增加相关，而PWB在控制后降低了AD的风险 沮丧。然而，这些重要关联的分子机制尚不清楚，并且是 该提议的重点。根据我们的研究和其他人的新兴证据，我们假设 关键microRNA（miRNA）的表达改变有助于抑郁症和PWB对AD风险的影响。 为了检验这一假设，我们建议研究一个独特的数据集 RUSH记忆和老化项目（地图）。这项前瞻性纵向研究每年收集有关的数据 抑郁，PWB，认知，身体健康和痴呆以及基因组，转录组和蛋白质组学数据 从背外侧前额叶皮层（DPFC）。我们提出了一项2阶段的遗传研究，以识别关键miRNA， 成绩单和与抑郁症相关的蛋白质，并与PWB分开，并检查它们如何联系 认知变化，AD痴呆和与痴呆有关的病理学。我们的发现数据集将是600 地图样品和复制集将为250个地图样本，然后进行所有850的联合分析。 在AIM 1中，我们建议分别通过 全基因组miRNA表达分析。然后，我们将确定这些miRNA如何与AD相关联 表型（即认知能力下降率，痴呆症的临床诊断和与痴呆有关的病理学）。 我们预计识别与抑郁症和AD显着相关的miRNA（称为dep-ad-- miRNA），以及PWB和AD（PWB-AD-MIRNA）。在AIM 2中，我们检查目标的成绩单水平 AD表型中的DEP-AD-MIRNA和PWB-AD-MIRNA。我们假设这些mRNA水平 目标将与AD表型相关。此外，我们将对共表达网络分析 现有的转录组识别表达模块和抑郁症和PWB的关键表达驱动因素， 分别地。然后，我们将测试这些关键表达驱动因素是否与AD表型相关联。在AIM 3中，我们 将检查AD中DEP-AD-MIRNA和PWB-AD-MIRNA的下游靶标的蛋白质水平 表型。我们还测试了来自AIM 2的重要转录本的蛋白质水平是否与 广告表型。最后，我们将对现有的全球蛋白质组进行网络分析以识别新颖 分别用于抑郁症和PWB的蛋白质组学驱动因素，并检查其与AD表型的关联。 该项目可能可以识别出可能不是AD痴呆的重要分子贡献者 通过其他方法明显，导致对AD和AD的机制和治疗目标的新见解 因此，对公共卫生有重要的持续影响。