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

项目总结 阿尔茨海默病(AD)是导致痴呆症的最常见原因，全世界有近600万美国人受到影响 65岁。阿尔茨海默病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习惯。导致新陈代谢综合征的生活方式特征 在AD患者中很常见，包括肥胖、血脂异常和糖尿病。睡眠模式的改变可能是 阿尔茨海默病进展的最早迹象和睡眠剥夺与抗体和睡眠的积累有关 脑和脑脊液(CSF)中的tau蛋白。确定代谢综合征的遗传危险因素 睡眠障碍可以为AD遗传和风险提供新的见解。 GWASMeta分析确认PPP1R3B是一个新的推测的AD基因座，但没有发现 了解PPP1R3B在AD中的作用、细胞类型表达或作用机制。我们的实验室正在调查 PPP1R3B与非酒精性脂肪性肝病相关的分子和生化机制 (NAFLD)，常见于代谢综合征。新出现的数据表明NAFLD本身可能是一个风险因素 对于AD，通过阻碍外周抗体的清除，导致脑内抗体蓄积增加。我们目前的情况 研究表明，小鼠肝脏Ppp1r3b缺失可概括代谢综合征的多个方面 并导致NAFLD，因此PPP1R3B基因变异的代谢后果可能 增加了发展成AD的风险。最近发现pp1r3b参与调节昼夜节律基因。 表情。昼夜节律影响多种与AD相关的因素，包括血糖和血脂 新陈代谢和睡眠-觉醒周期。对基因表达数据库的研究表明，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可能具有与肝功能所描述的完全不同的生化机制。鉴于此， Ppp1r3b的意想不到的新潜在功能，我们建议将现有的研究方案扩展到 包括一项关于Ppp1r3b表达在AD中的作用的初步研究。在本研究中，我们的目标是 探讨Ppp1r3b在AD中表达的两种可能途径：目的1：确定肝脏Ppp1r3b对AD的影响 利用肝细胞特异性研究神经炎症和AD相关认知功能减退的代谢失调 Ppp1r3b KO和过度表达小鼠模型。目的2：探讨Ppp1r3b在脑出血中的潜在作用 昼夜节律及其与阿尔茨海默病的关系，使用小胶质细胞模型并检验全脑的影响 小鼠体内Ppp1r3b缺失。这些先导实验产生的数据将阐明肝细胞的作用 小胶质细胞Ppp1r3b在阿尔茨海默病小鼠中的表达特征。有可能建立一部全新的小说 Ppp1r3b在调节昼夜节律中的作用。这些发现将被用来支持未来的研究建议 为了进一步研究PPP1R3B Gwas与AD的相关性。

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.