# Deciphering molecular mechanisms that underlie brain endothelial cell dysfunction with APOE4

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2021 · $389,184

## Abstract

ABSTRACT
The blood brain barrier (BBB) plays a key role in maintaining brain integrity. The BBB prevents unwanted
molecules from entering the brain and supplies essential nutrients and signaling molecules to meet the high-
energy demand of neurons. Specialized brain endothelial cells (BECs) are central to the function of the BBB.
BECs express tight junction proteins that limit paracellular permeability to factors from the blood and BECs
form an extensive network with every neuron supplied by its own capillary. Current research has demonstrated
that BEC dysfunction is prevalent in aging leading to both higher leakiness and lower vessel coverage. These
changes may affect cognition in two ways: 1) Higher BEC leakiness to plasma proteins can lead to damage of
neurons directly or through bystander effects (e.g. glial mediated neuroinflammation) and; 2) Lower vessel
coverage limits the supply of essential nutrients to neurons. An important question is the extent and underlying
mechanism(s) that genetic factors risk factors for cognitive decline in aging modulate BEC function. One such
factor is APOE genotype, as APOE4 is associated with cognitive dysfunction compared to APOE3 in older
adults. Our in vivo data supports that APOE4 is associated with BEC dysfunction in aging, and a potential
underlying mechanism has emerged. Angiogenic growth factors are important for controlling leakiness and
maintaining vessel coverage through actions on BEC function. Our data suggest a mechanistic interaction
exists between APOE and epidermal growth factor (EGF) pathways. Specifically, that apolipoprotein (apoE) E3
produced by BECs signals in an autocrine/paracrine-like manner via apoE receptors to increase the production
of EGF, resulting in improved BEC function. However, this process is impaired with apoE4. Based on these
data, we propose to test the hypothesis that failure in apoE4 receptor signaling leads to BEC dysfunction and
that EGF can ameliorate this dysfunction. We further propose that this mechanism contributes to BEC
dysfunction observed in Alzheimer's disease (AD) patients. APOE4 is the greatest genetic risk for sporadic AD,
increasing risk up to 12-fold compared to APOE3 and high levels of amyloid-β(Aβ) in the brain are a major
component of AD. Our preliminary data suggest Aβ exacerbates APOE4 associated BEC dysfunction. Thus,
our experiments will evaluate whether APOE4 increases BEC dysfunction and whether Aβ exacerbates this
dysfunction in vivo. We will examine the possibility that a failure in apoE receptor signaling underlies BEC
dysfunction with apoE4, and that this disruption is exacerbated by Aβ. Finally, we will test whether peripheral
administration of EGF reduces deficits in BEC and cognitive function. Our studies would implicate apoE4
associated BEC dysfunction as an important pathway contributing to cognitive decline in both aging and AD

## Key facts

- **NIH application ID:** 10061520
- **Project number:** 5R01AG061114-03
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Leon Maing Tai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $389,184
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10061520

## Citation

> US National Institutes of Health, RePORTER application 10061520, Deciphering molecular mechanisms that underlie brain endothelial cell dysfunction with APOE4 (5R01AG061114-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10061520. Licensed CC0.

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