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

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $486,058

## 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 (AD). 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. These cellular clocks are synchronized to the external environment by the central
clock in the suprachiasmatic nucleus in the brain. Cellular circadian clocks are particularly robust in glial cells,
regulating cellular activation and inflammatory responses in both astrocytes and microglia. We have found that
the circadian clock protein BMAL1 regulates astrocyte activation, neuroinflammation, and amyloid plaque
deposition in mice. We have also found that amyloid plaques cause large-scale alterations in circadian
transcriptional rhythms in astrocytes. Thus, we will address the bidirectional relationship between circadian
clock disruption and AD-related pathology in mouse models of AD, focusing on how the central and cellular
clocks regulate astrocyte responses to protein aggregation. Using novel methods to interrogate cell type-
specific transcription in vivo, we will compare the effects of central vs. cellular clock disruption on circadian
function in astrocytes, both in healthy brain and in a model of AD. We then evaluate the effects of central and
cellular clock disruption on pathology caused by Aβ and tau, and determine specific clock-regulated pathways
in astrocytes that control protein degradation and inflammation. By understanding the bidirectional relationship
between circadian rhythms and astrocyte function, we hope to identify novel therapeutic targets to prevent
protein aggregation and inflammation in Alzheimer’s Disease.

## Key facts

- **NIH application ID:** 10367153
- **Project number:** 2R01AG054517-06
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Erik Steven Musiek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $486,058
- **Award type:** 2
- **Project period:** 2017-07-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10367153

## Citation

> US National Institutes of Health, RePORTER application 10367153, ROLE OF GLIAL CIRCADIAN CLOCK DYSFUNCTION IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE (2R01AG054517-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10367153. Licensed CC0.

---

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