# The effect of circadian rhythm disruptions on the angiogenic response to hypoperfusion in the AD brain

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $759,102

## Abstract

PROJECT SUMMARY/ABSTRACT
Although the pathophysiology of Alzheimer’s Disease (AD) is complex and multifactorial, vascular comorbidities
and cerebrovascular insufficiency occur in almost two-thirds of AD patients. However, how cerebrovascular
insufficiency interacts with and contributes to AD remains poorly understood. Recently, the brain vasculome (i.e.
transcriptome profiles of cerebral endothelial cells and pericytes) has been proposed as a conceptual
framework to investigate vascular mechanisms in CNS diseases. In response to RFA-AG-23-014 (Mechanisms
of Brain Hypoperfusion in AD/ADRD), we propose to test the hypothesis that cerebrovascular insufficiency
perturbs the AD brain vasculome, eventually leading to cognitive impairment.
The normal brain compensates for hypoperfusion by inducing endogenous vascular remodeling and
angiogenesis. The presence of AD interferes with endogenous angiogenesis and vascular recovery in response
to hypoperfusion, and this exacerbates AD progression and worsens the AD brain vasculome. Because
circadian rhythms and circadian genes are known to regulate angiogenesis, we further hypothesize that AD
disrupts circadian homeostasis in the brain vasculome, thus interfering with the endogenous angiogenic
response to hypoperfusion.
The importance of investigating these interactions between AD, vascular responses, and circadian rhythms is
emphasized by our pilot data. For example, we show a greater difference in transcriptome profiles of cerebral
endothelial cells and pericytes of wild-type vs AD mice when tested during the active (awake) phase compared
to the inactive (sleep) phase. For testing our hypotheses, we propose three integrated aims. Aim 1 will show
that AD brains exhibit a lower capacity of compensatory angiogenesis in response to hypoperfusion, and Aim 2
will show that circadian rhythms are disrupted in AD brains and that disrupted circadian rhythms suppress
angiogenic response. And finally, Aim 3 will examine whether re-normalizing circadian rhythms improves the
brain vasculome and promotes angiogenesis after hypoperfusion in AD mice.
Whether and how AD brains lose compensatory angiogenesis capacity after cerebral hypoperfusion is unknown.
Therefore, we have designed a multi-disciplinary multi-lab project to fill this gap of knowledge by examining how
perturbations in circadian rhythms disrupt the brain vasculome and worsen hypoperfusion in AD.

## Key facts

- **NIH application ID:** 10831536
- **Project number:** 5R01AG081841-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Ken Arai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $759,102
- **Award type:** 5
- **Project period:** 2023-05-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10831536

## Citation

> US National Institutes of Health, RePORTER application 10831536, The effect of circadian rhythm disruptions on the angiogenic response to hypoperfusion in the AD brain (5R01AG081841-02). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10831536. Licensed CC0.

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