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

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $406,248

## Abstract

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 f...

## Key facts

- **NIH application ID:** 10288770
- **Project number:** 3R01DK114291-04S1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Joseph A. Baur
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $406,248
- **Award type:** 3
- **Project period:** 2018-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10288770

## Citation

> US National Institutes of Health, RePORTER application 10288770, Mechanisms underlying the genetic association between PPP1R3B and Alzheimer's Disease (3R01DK114291-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10288770. Licensed CC0.

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