# Mechanisms of neurodegeneration in a porcine model of diet-induced CVD

> **NIH NIH R21** · TUFTS UNIVERSITY BOSTON · 2020 · $188,750

## Abstract

SUMMARY
The cognitive impairment associated with neurodegenerative diseases like Alzheimer's disease (AD) is the
major cause of disability in older adults. Epidemiological and clinical evidence suggests a strong link between
cardiovascular disease (CVD) and AD, supported by shared risk factors including hypertension, mid-life
hypercholesterolemia, presence of the apo E4 allele, smoking, and type 2 diabetes mellitus. Together, CVD
and AD are the most important causes of morbidity and mortality in the elderly and represent a major public
health and financial burden. It is well known that the atherosclerotic lesions leading to CVD and the brain
pathologies progressing to dementia and AD start decades before the appearance of the clinical signs and
symptoms of these diseases. While much has been learned about the macro- and micro-pathologic alterations
of the brain in fully-developed late-stage AD, very little is known about the molecular and metabolic changes
leading to the initial stages of neurodegeneration in AD and the associated gene expression and pathologic
alterations. Current animal models of AD are transgenic or knockout rodents and, while the use of these animal
models has advanced our understanding of some of the molecular aspects of AD, an important limitation is that
overexpression or absence of specific disease-related genes does not always mimic the full spectrum of the
disease in humans. The current proposal addresses the current need to identify animal models of
neurodegenerative disease, where the pathology is induced in a manner similar to humans and not by genetic
mutations. The objectives of this proposal are to identify the early brain gene expression and metabolic
pathways affected by diet-induced CVD and associated brain cell pathology. In order to address these
objectives, this proposal will utilize as experimental model the Ossabaw minipig, which we have recently
shown to be an excellent model of diet-induced CVD. Specifically, Ossabaw minipigs develop coronary
atherosclerosis when fed a human Western-style diet but not when fed a Mediterranean-style diet. Aim 1 will
identify the changes in pig brain vascular and tissue gene expression pathways associated with diet-induced
CVD using transcriptomic analysis. Aim 2 will identify the changes in pig brain metabolic pathways associated
with diet-induced CVD using untargeted metabolomics and targeted lipidomics. Aim 3 will characterize the
brain tissue and vascular histopathological alterations associated with diet-induced CVD using
immunohistochemistry analysis. Through these aims, we will test the hypothesis that regulatory networks in
endothelial dysfunction, inflammation and mitochondrial function serve as initiators in the cascade of metabolic
and gene expression changes induced in the brain by diet-induced CVD. The knowledge gained on the initial
triggers of neurodegeneration will lead to the identification of potential targets for early therapeutic
interventions.

## Key facts

- **NIH application ID:** 9880373
- **Project number:** 5R21AG058837-02
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** STEFANIA LAMON-FAVA
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $188,750
- **Award type:** 5
- **Project period:** 2019-03-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9880373

## Citation

> US National Institutes of Health, RePORTER application 9880373, Mechanisms of neurodegeneration in a porcine model of diet-induced CVD (5R21AG058837-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9880373. Licensed CC0.

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