Mechanisms underlying the genetic association between PPP1R3B and Alzheimer's Disease

PPP1R3B 与阿尔茨海默病之间遗传关联的潜在机制

• 批准号: 10288770
• 负责人: Joseph A. Baur
• 金额: $ 40.62万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288770
• 关键词: Affect; Age; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Amyloid Proteins; Amyloid beta-Protein Precursor; Astrocytes; Autopsy; Behavior assessment; Biochemical; Brain; Cell model; Cells; Cerebrospinal Fluid; Characteristics; Circadian Rhythms; Clinical; Confusion; Data; Databases; Dementia; Development; Diabetes Mellitus; Disease Progression; Dyslipidemias; Elderly; Environmental Risk Factor; Enzymes; Exhibits; Gene Expression; Genes; Genetic; Genetic Risk; Genetic Variation; Glucose; Glucose Intolerance; Glycogen; Habits; Hepatic; Hepatocyte; Heritability; Human; Immune; Immune response; Impaired cognition; Investigation; Knockout Mice; Life Style; Link; Lipids; Liver; Measures; Memory Loss; Meta-Analysis; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Microglia; Molecular; Mus; Nerve Degeneration; Neurons; Obesity; Pattern; Periodicity; Peripheral; Phagocytes; Phosphorylation; Pilot Projects; Plasma; Production; Protein phosphatase; Proteins; Reporting; Research; Research Proposals; Risk; Role; Sleep Deprivation; Sleep Wake Cycle; Sleep disturbances; Triglycerides; abeta accumulation; aged; causal variant; cell type; circadian; circadian regulation; cognitive function; daily functioning; data mining; disorder risk; exhaust; experimental study; gene expression database; genetic association; genetic risk factor; genome wide association study; glucose metabolism; glycogen metabolism; human old age (65+); inflammatory marker; insight; lipid metabolism; liver function; mouse model; neuroinflammation; neuron loss; neuronal metabolism; neurotransmission; non-alcoholic fatty liver disease; novel; novel therapeutic intervention; overexpression; presenilin; presenilin-1; presenilin-2; protein aggregation; risk variant; screening; sleep pattern; tau Proteins; transcriptome sequencing

PROJECT SUMMARY Alzheimer’s disease (AD) is the most common cause of dementia, affecting nearly 6 million Americans over the age of 65. The primary risk factor for AD is advanced age, followed by genetic risk variants, and then environmental factors and lifestyle habits. Lifestyle features that contribute to Metabolic Syndrome are highly prevalent in AD patients, including obesity, dyslipidemia, and diabetes. Altered sleep patterns may be one of the earliest signs of progressing AD, and sleep deprivation has been associated with accumulation of both Ab and tau proteins in the brain and cerebrospinal fluid (CSF). Identifying genetic risk factors for Metabolic Syndrome and sleep disturbances could provide novel insights into AD inheritance and risk. A GWAS meta-analysis identified PPP1R3B as a novel putative AD locus, however there is no current understanding of PPP1R3B’s role, cell-type expression, or functional mechanism in AD. Our lab investigates the molecular and biochemical mechanisms by which PPP1R3B is associated with non-alcoholic fatty liver disease (NAFLD) which often occurs in Metabolic Syndrome. Emerging data suggest NAFLD itself may be a risk factor for AD by impeding the clearance of peripheral Ab causing increased brain Ab accumulation. Our current research indicates that hepatic Ppp1r3b deletion in mice recapitulates multiple aspects of Metabolic Syndrome and contributes to NAFLD, and therefore the metabolic consequences of PPP1R3B genetic variation may contribute to the risk of developing AD. Recently, Ppp1r3b was implicated in regulating circadian gene expression. Circadian rhythms influence multiple factors associated with AD, including glucose and lipid metabolism, and sleep-wake cycles. Exploration of gene expression databases revealed that Ppp1r3b is expressed in the brains of mice and humans, and the cell-specific expression patterns suggest that brain Ppp1r3b might have an entirely distinct biochemical mechanism from that described in liver function. Given this unexpected new potential function of Ppp1r3b, we propose to expand our existing research proposal to include a pilot study investigation into the role of Ppp1r3b expression on AD. In this study we aim to investigate two potential avenues of Ppp1r3b expression on AD: Aim 1: Determine the effects of hepatic Ppp1r3b metabolic dysregulation on neuroinflammation and AD-associated cognitive decline using hepatocyte-specific Ppp1r3b KO and overexpression mouse models. Aim 2: Explore the potential involvement of Ppp1r3b in circadian regulation and the relationship to AD, using microglial cell models and examining the effect of whole body Ppp1r3b deletion in mice. Data generated from these pilot experiments will elucidate the roles of hepatocyte and microglia Ppp1r3b expression in AD characteristics in mice. There is potential to establish an entirely novel role for Ppp1r3b in regulating circadian rhythms. These findings will be used to support future research proposals to further examine the PPP1R3B GWAS association with AD.

项目摘要 阿尔茨海默氏病（AD）是痴呆症的最常见原因，影响了近600万美国人 年龄65岁。AD的主要风险因素是高龄，其次是遗传风险变异，然后是 环境因素和生活方式习惯。有助于代谢综合征的生活方式特征很高 在AD患者中普遍存在，包括肥胖症，血脂异常和糖尿病。改变睡眠方式可能是 进展广告的最早迹象和睡眠不足与AB和AB的积累有关 大脑中的tau蛋白和脑脊液（CSF）。确定代谢综合征的遗传危险因素 睡眠障碍可以为AD继承和风险提供新颖的见解。 GWAS荟萃分析将PPP1R3B识别为一个新型的假定广告基因座，但是没有电流 了解PPP1R3B在AD中的作用，细胞类型表达或功能机制。我们的实验室调查了 PPP1R3B与非酒精性脂肪肝病相关的分子和生化机制 （NAFLD）通常发生在代谢综合征中。新兴数据表明NAFLD本身可能是危险因素 通过阻碍清除周围AB的清除，导致大脑AB积累增加。我们的目前 研究表明，小鼠中的肝PPP1R3B缺失概括了代谢综合征的多个方面 并有助于NAFLD，因此PPP1R3B遗传变异的代谢后果可能 有助于发展广告的风险。最近，PPP1R3B在调节昼夜节律中暗示 表达。昼夜节律影响与AD相关的多个因素，包括葡萄糖和脂质 代谢和睡眠效果周期。基因表达数据库的探索表明PPP1R3B是 在小鼠和人类的大脑中表达，细胞特异性表达模式表明大脑 PPP1R3B可能具有与肝功能中描述的完全不同的生化机制。鉴于此 意外的PPP1R3B的新潜在功能，我们建议将现有的研究建议扩展到 包括对PPP1R3B表达在AD的作用的试点研究。在这项研究中，我们的目标是 研究PPP1R3B在AD上表达的两个潜在途径：AIM 1：确定肝PPP1R3B的影响 使用肝细胞特异性的神经炎症和与AD相关的认知下降的代谢失调 PPP1R3B KO和过表达鼠标模型。目标2：探索PPP1R3B的潜在参与 昼夜节律调节和与AD的关系，使用小胶质细胞模型并检查整个的效果 小鼠的身体PPP1R3B缺失。这些试验实验产生的数据将阐明肝细胞的作用 小鼠AD特征中的小胶质细胞PPP1R3B表达。有可能建立一个完全新颖的 PPP1R3B在调节昼夜节律中的作用。这些发现将用于支持未来的研究建议 进一步检查PPP1R3B GWAS与AD的关联。