# tPA and cerebrovascular regulation in a model of ß-amyloid pathology

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $423,750

## Abstract

PROJECT SUMMARY AND ABSTRACT:
There is accumulating evidence that alterations in cerebral blood vessels contribute to brain
dysfunction underlying Alzheimer's dementia (AD). Amyloid-beta is a major culprit in AD and
has deleterious effects on neurons and glia. Amyloid-beta also profoundly alters the regulation
of the cerebral microcirculation. However, little is known as to how amyloid-beta contributes to
altering the neurovascular regulation. This issue is particularly important considering the fact
that the brain is highly dependent on a ceaseless blood supply well matched to its metabolic
needs. Therefore, the goal of this grant application is to investigate how amyloid beta alters the
control mechanisms regulating the blood delivery to the brain and contributes to brain
dysfunction. We have recently found that the tissue plasminogen activator (tPA), an enzyme
best known for its involvement in vascular fibrinolysis, plays a key role in the mechanisms of
neurovascular regulation via its ability to modulate a critical neuron-to-vasculature signaling
pathway involving postsynaptic NMDA receptors (NMDAR), neuronal nitric oxide synthase
(nNOS), and nitric oxide. Therefore, we will test the hypothesis that the reduction in tPA
contributes to the neurovascular dysregulation and cognitive deficits induced by amyloid-beta in
mice overexpressing the amyloid precursor protein. The central hypothesis will be tested in 3
specific aims: (1) reduced tPA activity contributes to the alteration in neurovascular regulation
induced by amyloid-beta, (2) reduced tPA activity contributes to amyloid-beta-induced
neurovascular dysregulation by impairing nNOS-derived nitric oxide production dependent on
NMDA receptor, and (3) reduced tPA activity contributes to amyloid pathology and resulting
cognitive deficits. These specific aims will be achieved by employing a multidisciplinary strategy
combining in vitro molecular, biochemical, confocal and electron microscopic imaging, and in
vivo physiological and behavioral approaches.

## Key facts

- **NIH application ID:** 9840516
- **Project number:** 5R01NS097805-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Laibaik Park
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $423,750
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840516

## Citation

> US National Institutes of Health, RePORTER application 9840516, tPA and cerebrovascular regulation in a model of ß-amyloid pathology (5R01NS097805-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9840516. Licensed CC0.

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