# Overexpression of the amyloid precursor protein and cerebrovascular regulation

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $423,750

## Abstract

Alzheimer's disease (AD) is the leading cause of age-related cognitive impairment for which
there are no treatments. The structural and functional integrity of the brain requires a continuous
supply of oxygen and glucose through blood flow, well matched to its dynamic and regionally
diverse energy needs. Accordingly, neural activity increases blood flow in active brain regions, a
phenomenon termed functional hyperemia. Functional hyperemia depends in large part on the
link between NMDA receptor activity and neuronal production of the potent vasodilator nitric
oxide (NO), and requires tissue plasminogen activator (tPA) for its full expression. Increasing
evidence indicates that alterations in the regulation of the cerebral microcirculation play a
significant role in the pathogenesis of AD by reducing the cerebral blood supply, but the
mechanisms of such neurovascular dysfunction have not been fully elucidated. Most studies
have focused on the damaging cerebrovascular effects of Aβ. However, the role of tau, a key
pathogenic factor in AD, remains virtually unexplored. There is a strong rationale for
investigating tau. For example, in neurodegenerative diseases caused by tau mutations
(tauopathies), in which Aβ is not present, there is evidence of cerebrovascular dysfunction early
in the disease course, suggesting that tau exerts pathogenic vascular effects independently of
Aβ. Furthermore, hyperphosphorylated tau alters NMDA receptor signaling, which is essential
for the neuronal NO production driving functional hyperemia. Based on these scientific
premises, we will test the central hypothesis that pathological tau alters neurovascular coupling
by impairing the ability of NMDA receptors to trigger NO production, an effect occurring prior to
neurodegeneration and cognitive deficits. To this end, we will use state-of-the-art
multidisciplinary approaches to investigate neurovascular regulation in mouse models of
tauopathies, and in vitro approaches to explore the neurophysiological and molecular
mechanisms of the effects. We will test the following hypotheses: (a) Tau disrupts
neurovascular function prior to the onset of tau pathology and neurodegeneration; (b) The
neurovascular dysfunction induced by tau is due to uncoupling of NMDA receptor activity from
NO production; (c) NMDA receptor uncoupling from NO production and neurovascular
dysfunction result from a deficit in tPA caused by upregulation of the endogenous tPA inhibitor
PAI-1. The findings will begin to shed light on the vascular effects of pathological tau, thereby
filling a knowledge gap in our understanding of the neurovascular dysfunction of AD and other
tauopathies.

## Key facts

- **NIH application ID:** 10162672
- **Project number:** 5R01NS037853-24
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Costantino Iadecola
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $423,750
- **Award type:** 5
- **Project period:** 1998-07-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10162672

## Citation

> US National Institutes of Health, RePORTER application 10162672, Overexpression of the amyloid precursor protein and cerebrovascular regulation (5R01NS037853-24). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10162672. Licensed CC0.

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