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

项目摘要 阿尔茨海默氏病（AD）是痴呆症的最常见原因，在2010年影响了近600万美国人。 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 环境因素和生活习惯。生活方式的特点，有助于代谢综合征是高度 在AD患者中普遍存在，包括肥胖、血脂异常和糖尿病。睡眠模式的改变可能是 进展性AD的最早迹象，睡眠剥夺与Ab和 脑和脑脊液（CSF）中的tau蛋白。确定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。 一项GWAS荟萃分析将PPP 1 R3 B确定为一种新的推定AD基因座，但目前还没有关于PPP 1 R3 B的研究。 PPP 1 R3 B在AD中的作用、细胞类型表达或功能机制的理解。我们的实验室调查了 PPP 1 R3 B与非酒精性脂肪性肝病相关的分子和生化机制 （NAFLD），常发生于代谢综合征。新的数据表明NAFLD本身可能是一个风险因素 通过阻碍外周Ab的清除导致脑Ab蓄积增加来治疗AD。我们目前 研究表明，小鼠肝脏Ppp 1 r3 b缺失重现了代谢综合征的多个方面 并导致NAFLD，因此PPP 1 R3 B遗传变异的代谢后果可能 增加了AD的风险。最近，Ppp 1 r3 b参与调节昼夜节律基因 表情昼夜节律影响与AD相关的多种因素，包括血糖和血脂 新陈代谢和睡眠-觉醒周期。基因表达数据库的探索显示，Ppp 1 r3 b是 在小鼠和人类的大脑中表达，细胞特异性表达模式表明， ppp 1 r3 b可能有一个完全不同的生化机制，从肝功能。鉴于这种 意想不到的新的潜在功能Ppp 1 r3 b，我们建议扩大我们现有的研究建议， 包括Ppp 1 r3 b表达对AD作用的初步研究。在这项研究中，我们的目标是 研究Ppp 1 r3 b在AD中表达的两种潜在途径：目的1：确定肝脏Ppp 1 r3 b的作用 使用肝细胞特异性检测神经炎症和AD相关认知功能减退的代谢失调 Ppp 1 r3 b KO和过表达小鼠模型。目的2：探索Ppp 1 r3 b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体 小鼠体内Ppp 1 r3 b缺失。这些初步实验产生的数据将阐明肝细胞的作用， 和小胶质细胞Ppp 1 r3 b表达在小鼠AD特征中的作用。有可能建立一个全新的 Ppp 1 r3 b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 进一步研究PPP 1 R3 B GWAS与AD的关联。

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.