# tPA and Cerebrovascular Regulation in a Model of ß-amyloid Pathology

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $411,038

## Abstract

PROJECT SUMMARY AND ABSTRACT:
Alzheimer's disease and related dementias (ADRD) are disabling conditions that progressively
deprive affected individuals of their cognitive functions, ultimately leading to their inability to
perform basic activities of daily living. The brain depends on continuous and well-regulated
delivery of energy substrates through the brain blood flow, which is accomplished by elaborate
neurovascular control mechanisms that always ensure sufficient cerebral perfusion. One such
mechanism, termed functional hyperemia, couples local neural activity with the delivery of blood
flow and requires tissue plasminogen activator (tPA) for its full expression, since tPA enables
the production of the potent vasodilator nitric oxide during glutamatergic synaptic activity.
Neurovascular alterations are observed early in the disease course of ADRD and may promote
the expression of cognitive impairment. Amyloid-beta, a significant pathogenic contributor to AD,
suppresses functional hyperemia by upregulating the tPA inhibitor PAI-1 resulting in a reduction
in tPA activity. However, the cellular sources of PAI-1 remain unclear, and their identification
would suggest new approaches to rescue the neurovascular dysfunction induced by amyloid-
beta. Perivascular macrophages (PVM), brain resident myeloid cells distinct from microglia
located in the perivascular space, can produce large amounts of reactive oxygen species (ROS)
which are critical drivers of PAI-1 upregulation. Therefore, we will test the central hypothesis
that PVM are the major source of the PAI-1 that leads to tPA deficiency, neurovascular
dysfunction, and cognitive deficits induced by amyloid-beta. This hypothesis will be tested in 3
specific aims: (1) PVM are the source of PAI-1 mediating tPA deficiency and neurovascular
uncoupling induced by amyloid-beta, (2) PVM CD36 and Nox2, which are responsible for the
ROS production in these cells, mediate the PAI-1 upregulation, and (3) PVM PAI-1 contributes
to the effects of long-term accumulation of amyloid-beta. These specific aims will be
accomplished by employing tour de force approaches, including in vivo and in vitro techniques.
The application will widen our knowledge basis for the cellular mechanisms of harmful
neurovascular effects of amyloid-beta.

## Key facts

- **NIH application ID:** 10786127
- **Project number:** 5R01NS097805-07
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Laibaik Park
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $411,038
- **Award type:** 5
- **Project period:** 2018-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10786127

## Citation

> US National Institutes of Health, RePORTER application 10786127, tPA and Cerebrovascular Regulation in a Model of ß-amyloid Pathology (5R01NS097805-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10786127. Licensed CC0.

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