# Microglial regulation of cerebrovascular cholesterol metabolism: implications forAlzheimers disease

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $433,875

## Abstract

ABSTRACT
 Alzheimer's disease (AD) is a devastating chronic neurodegenerative disease and the leading cause of
dementia in older adults. One of the hallmark pathologies of AD is accumulation of extracellular amyloid-beta
(Aβ) “plaques”. These plaques can form both in the parenchyma as well as in the walls of meningeal and
cerebral blood vessels. Vascular Aβ plaques, termed cerebral amyloid angiopathy (CAA), are present in up to
98% of AD patients and can cause stroke, dementia, inflammation, cortical microbleeds, and hemorrhage.
Despite the serious clinical ramifications of CAA, it remains unclear why plaques develop in vascular walls.
With therapeutic prevention of CAA as a long-term goal, this proposal aims to investigate the role of microglia
in regulating cholesterol homeostasis in endothelial cells (ECs)––the cells that make up the walls of blood
vessels. There are several epidemiological links between cholesterol and AD, yet the specific mechanisms
underlying this association are unknown. Our preliminary data show that microglial depletion causes
upregulation of cholesterol synthesis enzymes in brain ECs. Because a higher cellular levels of esterified
cholesterol have been shown to increase Aβ production, we hypothesize that microglial dysfunction in AD
disrupts brain EC cholesterol metabolism, driving Aβ production and secretion, thereby potentiating CAA in AD.
This proposal will test this novel hypothesis and will also determine how dietary cholesterol modulates brain
EC cholesterol metabolism. Specifically, we will test how microglial depletion affects cholesterol synthesis in
other neural cell types by quantifying expression of cholesterol synthesis machinery in astrocytes, neurons,
and oligodendrocytes. As brain ECs lie at the interface between the brain and the blood, we will also
investigate how increasing dietary cholesterol with a high fat diet modulates cholesterol metabolism in brain
ECs. Finally, we will assess the separate and combined effects of microglial depletion and high fat diet on
vascular pathology in a model of AD. Taken together, the experiments proposed here will advance our
understanding of the association between cholesterol and AD, particualrly CAA. Furthermore, these data will
identify whether therapeutic regulation of cholesterol synthesis or efflux specifically in brain ECs could be a
successful clinical strategy for preventing CAA.

## Key facts

- **NIH application ID:** 10128176
- **Project number:** 1R21AG067035-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Richard Daneman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $433,875
- **Award type:** 1
- **Project period:** 2020-09-11 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128176

## Citation

> US National Institutes of Health, RePORTER application 10128176, Microglial regulation of cerebrovascular cholesterol metabolism: implications forAlzheimers disease (1R21AG067035-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10128176. Licensed CC0.

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