# Cerebral functional hyperemia responses induced by capillary NMDA receptors are disrupted by amyloid-beta accumulation

> **NIH NIH R00** · UNIVERSITY OF ARIZONA · 2020 · $249,000

## Abstract

Project Summary
Accumulation of the protein amyloid-β is a hallmark of the condition called cerebral amyloid angiopathy, and is
observed in approximately 80% of patients with Alzheimer’s disease, a most prevalent cause of dementia.
Although dementia is a consequence of loss of neurons, studies show that impairment in the control of blood
flow to active regions of the brain occurs before neuronal death is evident. Neurons have a limited capacity to
store energy and nutrients necessary for their optimal function, thus relying on the cerebral circulation for delivery
of necessary nutrients. One hallmark of the brain circulation is its ability to remarkably control blood perfusion to
regions of increased neuronal activity, a process known as functional hyperemia. This localized increase in blood
perfusion to match neuronal activity is a consequence of neurovascular coupling (NVC), in which neurons, glial
cells (mainly astrocytes) and endothelial cells (EC) act in concert to promote vasodilation of upstream arterioles,
shunting blood to active neurons. Functional hyperemia and NVC are known to occur for more than a century,
but most of its mediators and cellular effectors remain unknown. Active neurons release a plethora of transmitters
that activates astrocytes, a type of non-neuronal cells in the brain. Astrocytes, on the other hand, emit projections
that envelop cerebral capillaries, called astrocytic end-feet. Therefore, substances released from activated
astrocytes can then act on cerebral capillary EC to signal to the vasculature the metabolic status of a particular
neuronal population. Capillary EC do not possess contractile activity, thus control of blood perfusion through a
capillary bed will fall on the contractile member of the cerebral microvascular tree: the upstream parenchymal
arteriole. For capillary EC to cause dilation of upstream arterioles, it is necessary that a sensor in capillary EC
initiates a signal that is rapidly transmitted to upstream arterioles. This project focuses on the effects of one of
such signals, the N-Methyl-D-Aspartate receptor (NMDAR) and its role in generating a propagated vasodilatory
response from the capillaries to arterioles in the brain. Further, studies proposed here will also investigate how
amyloid-β can interfere in this essential process in the brain, as amyloid-β was shown to reduce NMDAR activity
in neurons. Thus, it is possible that one of the mechanisms by which amyloid-β impairs NVC in patients with
cerebral amyloid angiopathy is by reducing the activity of NMDAR in cerebral capillary EC.

## Key facts

- **NIH application ID:** 9851945
- **Project number:** 5R00HL140106-04
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Paulo W Pires
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2017-12-18 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851945

## Citation

> US National Institutes of Health, RePORTER application 9851945, Cerebral functional hyperemia responses induced by capillary NMDA receptors are disrupted by amyloid-beta accumulation (5R00HL140106-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9851945. Licensed CC0.

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