# Functional crosstalk between brain circadian oscillators and AD pathology in mouse models.

> **NIH NIH R03** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $154,834

## Abstract

PROJECT SUMMARY / ABSTRACT
 The circadian clock is our intrinsic timer where the hypothalamic suprachiasmatic nuclei (SCN) serves as a
central pacemaker to orchestrate cell-autonomous oscillators throughout the body. The clock plays fundamental
roles in driving rhythmic tissue and systemic functions such as cognition and sleep. Dysregulated physiological
rhythms, including sleep/wake cycles, are increasingly appreciated as a key pathophysiological factor associated
with Alzheimer's disease (AD). Disruption of the circadian clock has been shown to cause abnormal gene
expression and neurodegeneration, and recent studies indicated adverse impact on amyloid dynamics in mice
lacking the core clock component BMAL1. However, whether and by what cellular and molecular mechanisms
the circadian clock contributes to AD pathology and disease progression remains poorly understood. We
previously generated two circadian reporter mouse lines, Per2::Luc and Per2::LucSV, corresponding to normal
and enhanced circadian oscillation respectively. Combining this powerful reagent set with single-cell
bioluminescence imaging, we propose to test the central hypothesis that there is a functional crosstalk between
circadian oscillators in the brain and AD pathology, and enhancing circadian oscillation can decelerate disease
progression via regulation of gene expression and protein aggregation. We propose two specific aims. In Aim 1,
we will determine a reciprocal relationship between brain clocks and AD progression. We will first address the
question whether AD progression dysregulates SCN oscillators using Per2::Luc/APP-PS1 mice as a model of
early-onset familial AD expressing a circadian reporter. We will perform single-cell bioluminescence imaging to
determine a possible AD-induced deterioration in individual oscillators and coupling in the SCN, as well as phase
relationship between SCN and cortex/hippocampus oscillators. Using an environmental jet-lag paradigm to
disrupt the light input pathway to the SCN and consequently circadian rhythms, we will investigate whether
circadian disruption in turn exacerbates disease progression. In Aim 2, we will address the hypothesis that
activation of the oscillator can be deployed as an interventional strategy against AD. Using Per2::LucSV/APP-
PS1 mice, we will determine whether enhanced circadian oscillation ameliorates AD behavior and Abeta and tau
pathology and sustains robustness in circadian behavioral and sleep architecture. We will further determine the
effects of circadian enhancement on putative clock-controlled AD genes. The innovations of this project include
a novel conceptual framework of the circadian oscillator as a modifiable causal factor against AD, the new
methodologies including Per2::LucSV and single-cell bioluminescence imaging, the interventional strategy of
activating the oscillator to delay AD progression, and the elucidation of new molecular and cellular mechanisms
linking the circadian oscillator and AD. ...

## Key facts

- **NIH application ID:** 9902300
- **Project number:** 5R03AG063286-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Seung-Hee Yoo
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $154,834
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9902300

## Citation

> US National Institutes of Health, RePORTER application 9902300, Functional crosstalk between brain circadian oscillators and AD pathology in mouse models. (5R03AG063286-02). Retrieved via AI Analytics 2026-06-23 from https://api.ai-analytics.org/grant/nih/9902300. Licensed CC0.

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