# Effects on the brain microvasculature of age and circadian rhythm as risk factors for Alzheimer's disease

> **NIH NIH R56** · TULANE UNIVERSITY OF LOUISIANA · 2022 · $589,530

## Abstract

Aging and circadian/diurnal rhythm have independent effects on energy production (OXPHOS vs. glycolysis)
and mitochondrial fuel choice (glucose/fatty acids), but interactions and underlying mechanisms have not
been examined in the cerebral microcirculation. Studies on energy production of the cerebral vasculature have
been performed during the working day for the convenience of laboratory workers, which is, contrariwise, the
inactive, fasting time for rodents when glucose levels and levels of alternative fuels for mitochondria fluctuate
widely. Recent papers have highlighted the importance of diurnal rhythm on disease occurrence such as
strokes and for the selection of optimal timing of chemotherapy. We will improve the understanding of this
important area using innovative methods and approaches developed by our laboratory, supported by exciting,
novel findings, to ascertain for the first time mitochondrial and glycolytic dynamics of large (arteries) and
microvessels (MVs, end arterioles, capillaries, venules) during aging in mice. Importantly, we made the
unexpected finding that fibrinogen levels in brain MVs increase during aging, probably transported by
circulating exosomes, and that fibrinogen induces oxidative stress and further disruption of tight
junctions in brain endothelial cells. We postulate that mitochondrial dysfunction induced fibrinogen
accumulation and ROS production in brain MVs leads to activation of microglia and accumulation of beta
amyloid. Relevance to PAR-19-070: The brain microcirculation, including the blood-brain barrier (BBB), faces
constant metabolic challenges while responding to physiological and nutritional status, which are exacerbated
by diurnal rhythm and aging. A focus on cerebral MVs is warranted because adverse changes in energy
production in the microcirculation promote cognitive impairment, strokes, vascular dementia, and Alzheimer’s
disease (AD), and because fibrinogen accumulation causes beta amyloid accumulation and microglia
activation—hallmarks of AD. Our studies are conceptually innovative based on our novel discoveries in
and technically innovative due to application of new technologies. Our hypothesis is that age- or time-
related mitochondrial dysfunction is a critical target for potential therapies to protect the MVs and
brain against neurological damage and cognitive impairment. We have 2 aims. Aim 1: Elucidate
mechanisms of mitochondrial, glycolytic, and cellular changes in brain MVs during aging. We will: a)
determine mitochondrial and vascular characteristics of MVs and BBB status using in vivo multiphoton
imaging in mice at 4–6 (young), 12–14 (middle age) and 18‒24 (old) months of age; b) determine the effects
of aging on glycolysis and OXPHOS, mitochondrial fuel choice, and mitoROS in MVs and arteries; c)
investigate the role of fibrinogen in promoting mitochondrial changes of MVs and arteries during aging; and d)
explore treatment modalities for protecting mitochondria and the brain circula...

## Key facts

- **NIH application ID:** 10670497
- **Project number:** 1R56AG075988-01A1
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** DAVID W BUSIJA
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $589,530
- **Award type:** 1
- **Project period:** 2022-08-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10670497

## Citation

> US National Institutes of Health, RePORTER application 10670497, Effects on the brain microvasculature of age and circadian rhythm as risk factors for Alzheimer's disease (1R56AG075988-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10670497. Licensed CC0.

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