# Role of REV-ERB Proteins in Neuroinflammation and Alzheimer's Disease

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $418,139

## Abstract

PROJECT SUMMARY/ABSTRACT
Role of REV-ERB Proteins in Neuroinflammation and Alzheimer’s Disease
Circadian rhythm disruption is observed in Alzheimer’s Disease, and emerging data suggests that circadian
dysfunction may contribute to the neurodegenerative process. However, mechanisms connecting circadian
dysfunction to Alzheimer’s Disease-related neurodegeneration remain unclear. On a molecular level, core
circadian clock genes mediate circadian rhythms, and also serve as critical transcriptional and metabolic
regulators in a variety of organs, including the brain. We have shown that genetic disruption of the circadian
clock by deletion of the master clock gene Bmal1 causes severe gliosis, oxidative damage, and synaptic
degeneration in mouse brain, suggesting a link between core clock function and neurodegeneration. We have
subsequently found that the deletion of REV-ERBα, a component of the core clock which is directly regulated
by BMAL1, also causes spontaneous microglial activation and neuroinflammation. Our data shows that REV-
ERBα expression is suppressed in the cortex of amyloid plaque-bearing APP/PS1 mice, a model of
Alzheimer’s Disease, and in activated microglia. REV-ERBα and its homolog REV-ERBβ are nuclear receptors
which, aside from their function in the circadian clock, have been implicated in regulation of inflammation and
metabolism. We hypothesize that REV-ERBs serve to link the circadian clock to neuroinflammation and
neurodegeneration. We will examine the cell-autonomous function of REV-ERBs in regulating microglial
activation and neuroinflammation, and identify transcriptional pathways regulated by REV-ERBs in microglia.
We will determine if REV-ERBs control microglial synaptic phagocytosis in the brain via transcriptional
regulation of complement genes. Because they are nuclear receptors, REV-ERBs can be manipulated
pharmacologically. Thus, we will examine the effects of cell type specific genetic deletion of REV-ERBs, or
activation or inhibition of REV-ERB function with small molecule agonists, on neuroinflammation and
neurodegeneration in a mouse model of Alzheimer’s Disease. These studies will shed new light on molecular
mechanisms linking the circadian clock and Alzheimer’s Disease-related neurodegeneration, and illuminate the
novel strategy of directly targeting the circadian clock for neuroprotection.

## Key facts

- **NIH application ID:** 10138964
- **Project number:** 5R01AG063743-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Erik Steven Musiek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $418,139
- **Award type:** 5
- **Project period:** 2020-04-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10138964

## Citation

> US National Institutes of Health, RePORTER application 10138964, Role of REV-ERB Proteins in Neuroinflammation and Alzheimer's Disease (5R01AG063743-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10138964. Licensed CC0.

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