# Phenotypes and mechanisms of pulmonary hypertension-driven cognitive impairment and Alzheimer's disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $389,771

## Abstract

ABSTRACT.
The central focus of this application to is to mechanistically phenotype development of cognitive impairment and
Alzheimer’s disease in pulmonary hypertension (PH) using both in vitro and in vivo model systems. Reports by NIA
indicate that 6 million Americans have dementia caused by Alzheimer’s disease, which ranks as the 6th leading
cause of death. Alzheimer’s is characterized by progressive cognitive decline, which is pathophysiologically featured
by presence of extracellular amyloid β plaques and intraneural tau neurofibrillary tangles. Cognitive impairment and
Alzheimer’s have been linked to hypoxaemia/hypoxia, and blood-brain barrier (BBB) dysfunction that involves
endothelial barrier dysfunction. Hypoxia contributes to accumulation of amyloid β, hyperphosphorylation of tau, BBB
dysfunction and degeneration of neurons. Of note, respiratory limitation due to primary PH or secondary PH (e.g.
consequent to COPD), can lead to hypoxaemia/hypoxia in the brain, which would consequently cause cognitive
decline and phenotypes of Alzheimer’s. Elevated cytokine levels in PH patients (e.g. TNF-α, IL-6), can also induce
neuroinflammation and BBB dysfunction, hence potentially leading to development of Alzheimer’s. In preliminary
experiments we found that TNF-α and IL-6 induced dose-dependent downregulation of junctional proteins ZO-1 and
Occudin in human brain microvascular endothelial cells (HBMECs). Of note, NADPH oxidase 4 (NOX4) can be
activated by TNF-α in HBMECs. Our recent work indicates that NOX4 is selectively responsible for increased
oxidative stress and endothelial barrier dysfunction to mediate sepsis induced acute lung injury. We have also
recently identified a novel role of STUB1, in functioning as the specific E3 ligase responsible for regulating NOX4
protein stability. Therefore, in Aim 1 we will examine whether and how hypoxia and PH related cytokines induce
endothelial barrier dysfunction in HBMECs (changes in junctional proteins, endothelial permeability, and
transendothelial cell electrical resistance/TEER), which can in turn lead to BBB dysfunction and development of
cognitive impairment and Alzheimer’s. In the parent award, we have established a novel human disease like murine
model of PH with which the animals displayed dose-dependent increases in mPAP and RVSP, a full spectrum of
human disease like vascular lesions in the lung, and similar gene regulatory profiles as in human PH patients. In
Aim 2, we will employ this novel model of PH, and the classical hypoxia model of PH, to examine whether and how
induction of PH in aged mice will lead to cognitive impairment and features of Alzheimer’s. NOX4 knockout mice and
AAV-mediated STUB1 overexpression in vivo will be employed to examine if it will attenuate observed phenotypes
in PH mice. Disease-targeted treatment of PH will be employed to alleviate hypoxaemia/hypoxia to examine role of
hypoxia alongside measurements of cerebral tissue oxygenation and blood flow. Accomplis...

## Key facts

- **NIH application ID:** 10498427
- **Project number:** 3R01HL154754-03S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Hua Linda Cai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $389,771
- **Award type:** 3
- **Project period:** 2020-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10498427

## Citation

> US National Institutes of Health, RePORTER application 10498427, Phenotypes and mechanisms of pulmonary hypertension-driven cognitive impairment and Alzheimer's disease (3R01HL154754-03S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10498427. Licensed CC0.

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