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

项目总结

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.