# Neural activity dependent regulation of vascular: implications for Alzheimers disease

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $434,500

## Abstract

ABSTRACT
 Neurons rely on a continuous supply of oxygen and nutrients from the blood in order to function properly. To
meet this need, local blood flow increases immediately following neural activity, a phenomenon known as
neurovascular coupling (NVC). NVC involves is mediated by cellular interactions among neurons, astrocytes,
mural cells, and endothelial cells (ECs). While NVC has been studied for over a century, there is still much
unknown about this complicated process. A more active role for ECs in NVC has recently come to light, and
there is likely much more to uncover regarding EC contribution to NVC.
 As NVC is crucial for proper brain function, NVC dysfunction can lead to cognitive deficits. NVC declines in
aging and neurological diseases, with neural activity eliciting a weaker increase in blood flow. However, the
mechanisms underlying NVC dysfunction are unclear. Our preliminary data show that neural activity dynamically
regulates EC cholesterol synthesis and uptake. We also found that microglial depletion similarly alters EC
cholesterol metabolism. As cellular membrane cholesterol content alters the rigidity and cytoskeletal structure of
the cell, it may be that dynamic changes in EC cholesterol metabolism allow ECs to biophysically accommodate
NVC. Interestingly, disruptions in cholesterol homeostasis are a strong risk factor for AD. We hypothesize that
NVC leads to dynamic, activity-dependent changes in EC cholesterol metabolism, with microglia acting as
mediators between synapses and ECs. We further hypothesize that EC cholesterol dysregulation occurs with
NVC deficits in AD. In this proposal, we will first test the mechanistic link between NVC and EC cholesterol
homeostasis. We will then investigate how microglia interact with neural activity in regulating EC cholesterol.
Finally, we will assess neural activity-dependent regulation of EC cholesterol dynamics in a mouse model of AD
with cerebral amyloid angiopathy. Together, the proposed experiments will advance our mechanistic
understanding of the novel finding that neural activity regulates EC cholesterol metabolism. 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 NVC deficits in aging and AD.

## Key facts

- **NIH application ID:** 10430716
- **Project number:** 1R21AG077148-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Richard Daneman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $434,500
- **Award type:** 1
- **Project period:** 2022-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10430716

## Citation

> US National Institutes of Health, RePORTER application 10430716, Neural activity dependent regulation of vascular: implications for Alzheimers disease (1R21AG077148-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10430716. Licensed CC0.

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