AD/ADRD Supplement to: Alterations of Sleep and Circadian Timing in Aging P01AG011412 Project 3.

NIH RePORTER · NIH · P01 · $390,776 · view on reporter.nih.gov ↗

Abstract

The goal of the proposed studies in this administrative supplement application is to test the hypothesis that specific sleep and circadian disturbances characteristic of aging and early-stage Alzheimer’s disease (AD) contribute to AD and ADRD cognitive disturbances, and targeting these can be used as a countermeasure to aging- and AD- related dementia. AD is associated with profound disruptions in circadian rhythms and sleep, which exacerbate neuropathology and dementia via mechanisms involving neurophysiology, synaptic plasticity, neuroinflammation, and metabolic pathways. In a study of a widely used genetic model of AD, 5xFAD mice, we found elevated intensity of theta (4-8 Hz) oscillations during rapid-eye-movement (REM) sleep at all times of the day, blunting the diurnal rhythms of theta intensity that can be observed in wildtype mice. These circadian and sleep changes were observed at the early symptomatic stage, tightly linked to acetylcholine neurotransmission and memory consolidation, and with striking resemblance to REM sleep power spectrum changes in patients with preclinical and mild-to-moderate AD. Remarkably, our current P01AG011412 studies found that aged mice exhibit the same alternations in REM theta as observed in the young early symptomatic 5xFAD mice. Our program project studies (Project 3) are designed to test the hypothesis that circadian phase-restricted feeding as an aging countermeasure to boost circadian amplitude and alignment, sleep, and metabolic homeostasis. Given our new preliminary observations, we propose to test the hypothesis that circadian phase-restricted feeding is also a countermeasure to restore disrupted circadian rhythms and abnormally elevated levels of REM theta oscillations, thereby alleviating aging- and AD- related cognitive disturbances. The proposed studies complement and extend the Project 3 studies; specifically, we will test whether circadian phase-restricted feeding restores the diurnal rhythms and proper levels of REM theta activity in aged and 5xFAD mice, and consequently improves memory performance. These studies build upon the experiments currently described in Aim 1 of Project 3, which focuses on the circadian, sleep, and metabolic benefits of circadian phase-restricted feeding in aged animals. Completion of these studies is expected to open new avenues to use behavioral approaches to mitigate the risks of and combat age- and AD -related dementia.

Key facts

NIH application ID
10294649
Project number
3P01AG011412-22S1
Recipient
NORTHWESTERN UNIVERSITY
Principal Investigator
Phyllis C. Zee
Activity code
P01
Funding institute
NIH
Fiscal year
2021
Award amount
$390,776
Award type
3
Project period
1997-02-01 → 2023-06-30