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) 和抑郁是改变阿尔茨海默病风险的重要因素 疾病（AD），一种记忆和认知进行性侵蚀的疾病。具体来说，抑郁症是 与 AD 痴呆风险增加相关，而 PWB 在控制后与 AD 风险降低相关 沮丧。然而，这些重要关联背后的分子机制尚不清楚，并且尚不清楚。 本提案的重点。根据我们和其他人的研究中出现的证据，我们假设 关键 microRNA (miRNA) 表达的改变导致抑郁症和 PWB 对 AD 风险的影响。 为了检验这一假设，我们建议研究来自 850 个人类死后大脑的独特数据集。 拉什记忆与衰老项目（MAP）。这项前瞻性纵向研究每年收集以下数据： 抑郁症、PWB、认知、身体健康和痴呆，以及基因组、转录组和蛋白质组数据 来自背外侧前额皮质（dPFC）。我们提出了一个两阶段的遗传学研究来鉴定关键的 miRNA， 转录本以及与抑郁症相关的蛋白质，并分别与 PWB 相关，并检查它们之间的关系 认知改变、AD 痴呆和痴呆相关病理。我们的发现数据集将是 600 MAP 样本和复制集将是 250 个 MAP 样本，然后对所有 850 个样本进行联合分析。 在目标 1 中，我们建议通过以下方法分别鉴定抑郁症和 PWB 特异的 miRNA： 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 表型（即认知能力下降的速度、痴呆症的临床诊断以及痴呆症相关的病理）。 我们预计会鉴定出与抑郁症和 AD 显着相关的 miRNA（称为 Dep-AD- miRNA），以及 PWB 和 AD (PWB-AD-miRNA)。在目标 2 中，我们检查目标的转录水平 AD 表型中的 Dep-AD-miRNA 和 PWB-AD-miRNA。我们假设这些基因的 mRNA 水平 目标将与 AD 表型相关。此外，我们将进行共表达网络分析 现有的转录组来识别抑郁症和 PWB 的表达模块和关键表达驱动因素， 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。在目标 3 中，我们 将检查 AD 中 Dep-AD-miRNA 和 PWB-AD-miRNA 下游靶标的蛋白质水平 表型。我们还测试了 Aim 2 中重要转录本的蛋白质水平是否与 AD表型。最后，我们将对现有的全球蛋白质组进行网络分析，以识别新的蛋白质组 分别研究抑郁症和 PWB 的蛋白质组驱动因素，并检查它们与 AD 表型的关联。 该项目有可能识别 AD 痴呆的重要分子贡献者，而这些因素可能不是 通过其他方法显而易见，从而对 AD 和治疗的机制和治疗目标产生新的见解 从而对公众健康产生重要且持续的影响。