# ROLE OF GLIAL CIRCADIAN CLOCK DYSFUNCTION IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $381,250

## Abstract

PROJECT SUMMARY/ABSTRACT
Role of glial circadian clock dysfunction in the pathogenesis of Alzheimer’s Disease
Chronic disruptions of the circadian system, manifesting as sleep disturbances, day-night confusion, and
“sundowning”, are well-described and debilitating symptoms of Alzheimer’s Disease. While circadian
disruption has long been considered a consequence of the degenerative process in AD, accumulating human
and mouse data suggest that circadian rhythm abnormalities may begin before overt cognitive symptoms, and
could play an important contributory role in AD pathogenesis. Circadian rhythms are generated in cells by
specific clock genes, which are expressed in neurons and glia throughout the brain and control 24-hour
oscillations in transcription. We have discovered that abrogating the function of the circadian clock via deletion
of the master clock gene Bmal1 in the brain causes severe gliosis, synaptic loss, neuroinflammation, and age-
related neurodegeneration. The circadian clock is particularly robust in glial cells, regulating cellular activation
and inflammatory responses in both astrocytes and microglia. Thus, we will address the bidirectional
relationship between circadian clock disruption and amyloid-beta (Aβ)-related pathology in cellular and mouse
models of AD, focusing on the function of clock genes in astrocytes and microglia. Using novel methods to
interrogate cell type-specific transcription in vivo and in vitro, we will test the hypothesis that Aβ directly impairs
the cellular circadian clocks of astrocytes and microglia in mouse AD models via an oxidative stress-dependent
mechanism. We will then determine if cell type-specific Bmal1 deletion in astrocytes and microglia,
respectively, will exacerbate neuroinflammation and synapse loss in the APP/PS1 mouse model of AD. We
have identified specific circadian-controlled pathways in astrocytes and microglia that may mediate these
effects, and will attempt to target these pathways therapeutically to mitigate neuroinflammation and synaptic
degeneration in aged APP/PS1 mice.

## Key facts

- **NIH application ID:** 10142329
- **Project number:** 5R01AG054517-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Erik Steven Musiek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10142329

## Citation

> US National Institutes of Health, RePORTER application 10142329, ROLE OF GLIAL CIRCADIAN CLOCK DYSFUNCTION IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE (5R01AG054517-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10142329. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*