# Potentiation of CAA-mediated endothelial dysfunction by cardiovascular risk factors

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2022 · $560,647

## Abstract

Project Summary/Abstract
Damage to the brain vasculature significantly contributes to Alzheimer's disease (AD) and dementia. In
addition to Cerebral Amyloid Angiopathy (CAA), which is present in more than 90% of AD patients and in many
cognitively normal elderly people, chronic cardiovascular (CV) risk factors are also known to impair brain
microvascular function. However, the interactive nature of CAA and chronic CV risk factors and the
mechanisms through which they contribute to cerebrovascular dysfunction and cognitive decline are poorly
understood. Our preliminary work identified molecular mechanisms responsible for amyloid beta (Aβ)-mediated
brain endothelial dysfunction. We propose to clarify the interplay between Aβ and overexpression/activation of
the TRAIL (TNF-related apoptosis inducing ligand) death receptors (DR) DR4 and DR5, unexplored targets of
enormous impact for cell stress/death. DR activation triggers mitochondrial dysfunction, with release of pro-
apoptotic factors and reactive oxygen species (ROS). Intriguingly, chronic CV risk factors associated with
cerebrovascular pathology, such as hypoperfusion, hypertension and hyperhomocysteinemia (HHC),
contribute to similar EC death and mitochondrial dysfunction pathways. We will test the hypothesis that
chronic CV risk factors, such as hypertension, HHC, and hypoperfusion, synergistically potentiate the
effects of cerebrovascular Aβ in CAA, enhancing TRAIL DR activation and mitochondrial dysfunction
in cerebral endothelial cells, and thus leading to neurovascular unit failure in Alzheimer's disease. In
Aim 1, using human cerebral endothelial cells in vitro, we will test the hypothesis that chronic CV risk factors
increase endothelial vulnerability to Aβ, potentiating DR- and mitochondria-mediated pathways. We will
analyze the relative contribution of hypoperfusion and HHC to Aβ-mediated endothelial DR activation,
mitochondrial toxicity and BBB permeability through molecular, biochemical and imaging approaches. In Aim 2,
we will test in vivo the hypothesis that chronic CV risk factors potentiate DR- and mitochondria-mediated
endothelial dysfunction and increase cerebrovascular amyloid burden in a mouse model of amyloidosis,
contributing to neurovascular and cognitive impairment. We will assess these mechanisms in Tg2576 mice
exposed to chronic CV risk factors (hypertension or HHC) before or after the development of CAA. We will
examine the effects of these stress pathways on BBB dysfunction, microhemorrhages, amyloid deposition,
neuroimmune activation, and cognitive function. In Aim 3 we will Test the hypothesis that manipulations that
decrease DR activation (DR silencing) and mitochondrial dysfunction (carbonic anhydrase inhibitors) will
prevent or reverse endothelial damage and BBB permeability induced by the combination of Aβ and chronic
cerebrovascular challenges that occur with CV risk. This study will reveal modifiable molecular mechanisms
underlying mixed cerebrovascular disea...

## Key facts

- **NIH application ID:** 10427355
- **Project number:** 5R01NS104127-06
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Silvia Fossati
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $560,647
- **Award type:** 5
- **Project period:** 2018-08-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427355

## Citation

> US National Institutes of Health, RePORTER application 10427355, Potentiation of CAA-mediated endothelial dysfunction by cardiovascular risk factors (5R01NS104127-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10427355. Licensed CC0.

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