# Neurovascular circadian oscillation in health and Alzheimer's disease

> **NIH NIH RF1** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $1,966,145

## Abstract

ABSTRACT
Alzheimer’s disease is a devastating chronic neurodegenerative disease and the leading cause of dementia in
older adults. One of the hallmark pathologies of Alzheimer’s disease is the accumulation of extracellular
amyloid-beta (Aβ) “plaques” throughout affected regions of the brain. In this grant we aim to understand how
two different but potentially inter-related physiological processes, circadian rhythms and the blood-brain barrier
(BBB), may interact to regulate the pathophysiology of Alzheimer’s disease. Biological rhythms are
orchestrated by the circadian clock and operate in most organisms, and allow for the anticipation of our
physiological needs to resonate with the alternating cycles of day and night. They include the daily rhythmicity
of the sleep-wake cycle, body temperature, and the metabolic activity of peripheral organs. In recent years, a
link between perturbation of circadian rhythms and Alzheimer’s disease was found in studies of both humans
and mice. Notably, people with Alzheimer’s disease exhibit profound disruptions to their 24 hour rhythms in
sleep-wake and activity patterns, often preceding the onset of clinical symptoms. It has also been found that
there is dysfunction of the BBB in Alzheimer’s patients early in the disease, and that biomarkers of this
dysfunction may be predictive of future cognitive decline in these individuals. The BBB is a term used to
describe the unique properties of the blood vessels that vascularize the central nervous system (CNS). This
barrier consists of physical, transport, signaling and metabolic properties that allow the endothelial cells (ECs)
that line the blood vessels to tightly regulate the movement of ions, molecules, and cells between the blood
and the brain, thus controlling the extracellular environment of the neural tissue. In our preliminary studies, we
have identified that there is a diurnal oscillation to BBB efflux transport, and that this rhythmicity is regulated by
the intrinsic expression of the circadian clock regulator BMAL1 within brain ECs. BBB efflux transport has been
shown to be critical in the clearance of Aβ from the brain. Therefore, we propose the hypothesis that loss of
BBB rhythmicity leads to dysfunction of Aβ clearance, exacerbating the pathophysiology of Alzheimer’s
disease. In this proposal we will address several important questions to understand how biological rhythms and
the BBB may interact, and how dysfunction of these two physiologies may play a role in the progression of
Alzheimer’s disease. First, we will use a series of series of structural, functional, and gene expression analyses
across different timepoints of day and night to determine which properties of the BBB display diurnal
oscillation. Second, we will determine whether the rhythmicity of the BBB is regulated by the intrinsic EC
circadian clock, the central circadian clock in the suprachiasmatic nucleus (SCN), and/or is entrained by light or
food. Third, using a mouse model of Alzhei...

## Key facts

- **NIH application ID:** 10655154
- **Project number:** 1RF1AG078241-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Richard Daneman
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,966,145
- **Award type:** 1
- **Project period:** 2023-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10655154

## Citation

> US National Institutes of Health, RePORTER application 10655154, Neurovascular circadian oscillation in health and Alzheimer's disease (1RF1AG078241-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10655154. Licensed CC0.

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