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.

项目概要 阿尔茨海默病 (AD) 是导致痴呆症的最常见原因，近 600 万美国人在过去几年中受到影响 65 岁。AD 的主要危险因素是高龄，其次是遗传风险变异，然后是 环境因素和生活方式特征对代谢综合征的影响很大。 AD患者中普遍存在的问题，包括肥胖、血脂异常和糖尿病，睡眠模式的改变可能是其中之一。 AD 进展的最早迹象，睡眠不足与 Ab 和 大脑和脑脊液 (CSF) 中的 tau 蛋白识别代谢综合征的遗传风险因素。 睡眠障碍可以为 AD 遗传和风险提供新的见解。 GWAS 荟萃分析将 PPP1R3B 确定为一种新的推定 AD 基因座，但目前尚无 了解 PPP1R3B 在 AD 中的作用、细胞类型表达或功能机制。 PPP1R3B 与非酒精性脂肪肝相关的分子和生化机制 (NAFLD) 经常发生在代谢综合征中，新出现的数据表明 NAFLD 本身可能是一个危险因素。 通过阻碍外周抗体的清除导致大脑抗体积累增加来治疗 AD。 研究表明小鼠肝脏 Ppp1r3b 缺失概括了代谢综合征的多个方面 并导致 NAFLD，因此 PPP1R3B 遗传变异的代谢后果可能 最近，Ppp1r3b 与调节昼夜节律基因有关。 昼夜节律影响与 AD 相关的多种因素，包括葡萄糖和脂质。 对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 鉴于此，Ppp1r3b 可能具有与肝功能中描述的完全不同的生化机制。 Ppp1r3b 意想不到的新潜在功能，我们建议将现有的研究计划扩展到 包括一项关于 Ppp1r3b 表达对 AD 作用的初步研究。 研究 Ppp1r3b 表达对 AD 的两种潜在途径：目标 1：确定肝脏 Ppp1r3b 的影响 使用肝细胞特异性代谢失调对神经炎症和 AD 相关认知能力下降的影响 Ppp1r3b KO 和过度表达小鼠模型 目标 2：探索 Ppp1r3b 在疾病中的潜在参与作用。 昼夜节律调节及其与 AD 的关系，使用小胶质细胞模型并检查整体的影响 小鼠体内 Ppp1r3b 缺失。这些试点实验产生的数据将阐明肝细胞的作用。 小鼠 AD 特征中小胶质细胞 Ppp1r3b 的表达有可能建立一种全新的方法。 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提案。 进一步检查 PPP1R3B GWAS 与 AD 的关联。