# Circadian clock gene Rev-erb in memory dysfunction in Alzheimer's disease

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $570,719

## Abstract

ABSTRACT/SUMMARY
Abnormal circadian rhythms of locomotor activities, body temperature, and hormonal levels not only are strongly
associated many neurodegenerative disorders including Alzheimer’s disease (AD) in both human patients and
animal models, but also precede cognitive deficits. However, it is unclear whether and how circadian disruption
per se causes cognitive deficits. It is also unclear whether and how the central circadian clock in the
suprachiasmatic nucleus (SCN) of the hypothalamus contributes to cognitive functions. Here we found that an
AD mouse model (APP NL-G-F) displays disrupted SCN molecular clock, including nuclear receptors Rev-erbα
and Rev-erbβ, and these molecular deficits proceed detectable cognitive dysfunctions. Circadian disruptions,
either by constant light exposure or by genetic deletion of Rev-erb in the SCN GABAergic neurons, cause
cognitive dysfunctions resembling those in APP NL-G-F mice. We hypothesize that disrupted circadian clock in
the SCN and alterations in SCN-originated neural circuitry contributes to cognitive dysfunctions in AD. We will
determine whether restoration of Rev-erb in the SCN rescues cognitive deficits in APP NL-G-F mice; determine
whether rhythmic SCN GABA neuron firing pattern is required to maintain normal cognitive functions; and
determine whether the GABA-SCN>PVT circuit regulates cognitive functions. Modern human society is featured
with nighttime light, nighttime feeding, social jetlag, and shift work. These circadian disruptions are highly
associated with memory deficits and neurodegenerative diseases, especially in aged populations. The proposed
study combines unique genetic animal models, light schedule manipulation, precise neuromodulation tools, and
cutting-edge molecular methods to address mechanisms of how circadian disruptions cause cognitive deficits.
Accomplishing these aims will provide novel insights into the pathophysiology of AD-related dementia, and lay
groundwork for chronotherapeutic interventions.

## Key facts

- **NIH application ID:** 10891768
- **Project number:** 4R01AG069966-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Zheng Sun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $570,719
- **Award type:** 4N
- **Project period:** 2021-02-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891768

## Citation

> US National Institutes of Health, RePORTER application 10891768, Circadian clock gene Rev-erb in memory dysfunction in Alzheimer's disease (4R01AG069966-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10891768. Licensed CC0.

---

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