# VCAM1 in brain endothelial cell activation in aging and Alzheimer's disease

> **NIH NIH F32** · STANFORD UNIVERSITY · 2020 · $64,926

## Abstract

Aging leads to the decline of brain structure and function which increases the susceptibility to neurodegenerative
disorders. Work from the Wyss-Coray lab support a cell non-autonomous and reversible mechanism of brain
aging regulated by the systemic milieu. Aged plasma drives brain aging in young mice as shown by the reduction
in hippocampal neurogenesis, increase in microglia reactivity, and decline in cognitive functions. While young
plasma reverses these hallmarks in aged mice. As the identity of the pro-youthful and pro-aging factors is being
revealed, it remains unclear how they signal into the brain across the highly impermeable blood brain barrier.
Recent work from our lab revealed that aged plasma upregulates on brain endothelial cells (BEC) the expression
of an adhesion protein VCAM1 (Vascular Cell Adhesion Molecule 1), which also increases during normal aging.
The genetic ablation of VCAM1 from BECs or its neutralization with a systemic antibody abolishes the effects of
aged plasma and reverses hallmarks of brain aging. This supports a crucial role for VCAM1 as a mediator of
age-related circulatory cues. Yet it remains unclear how VCAM1 alters BECs to drive brain aging. At a single cell
level, VCAM1 expressing BECs exhibit a high inflammatory profile compared to VCAM1 negative BECs and
blocking VCAM1 reduces brain inflammation suggesting that it may induce the inflammatory signaling in BECs.
In addition to aging, VCAM1 increases in the cerebral vessels of Alzheimer’s disease (AD) mice and colocalizes
with amyloid plaques and reactive microglia. Soluble VCAM1 also increases in AD patient plasma and highly
correlates with dementia severity and pathological hallmarks of AD. Based on these combined observations, this
proposal will test the hypothesis that increased VCAM1 disrupts brain endothelial cell signaling during aging and
promotes AD-like disease in mice. Aim 1 will determine whether VCAM1 induces the expression of inflammatory
genes in aged BEC using single cell transcriptomic analysis of hippocampal BECs and proteomic analysis of
microvessels. Experiments will be performed using aged mice where VCAM1 is genetically ablated from BECs
or neutralized with an antibody and using young mice where VCAM1 is overexpressed in BEC using the AAV2-
BR1 virus. Aim 2 will identify the mechanism behind which VCAM1 signals to induce BEC activation. Primary
BECs overexpressing wild-type or mutant VCAM1 will be cultured in the presence or absence of the VCAM1
ligand VLA-4 (very late antigen-4) to determine its effect on the expression of inflammatory genes in BEC. Mutant
VCAM1 that shows the highest reduction in BEC activation will be introduced in vivo using the AAV2-BR1 virus
to assess microglia reactivity and neural stem cell activity. Aim 3 will determine the role of VCAM1 in a mouse
model of AD. VCAM1 neutralizing antibody will be systemically introduced to determine its effect on amyloid
plaques, reactive microglia, cognitive deficits, and the...

## Key facts

- **NIH application ID:** 9991680
- **Project number:** 1F32AG067652-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Nathalie Khoury
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $64,926
- **Award type:** 1
- **Project period:** 2020-05-15 → 2023-05-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991680

## Citation

> US National Institutes of Health, RePORTER application 9991680, VCAM1 in brain endothelial cell activation in aging and Alzheimer's disease (1F32AG067652-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9991680. Licensed CC0.

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