# Integrin mediated regulation of lymphatics during aging and neurodegeneration

> **NIH NIH R21** · CLEVELAND CLINIC LERNER COM-CWRU · 2022 · $442,750

## Abstract

PROJECT SUMMARY/ABSTRACT
 This project aims at understanding how the integrin CD49a participates in age-associated loss of meningeal
lymphatic function and in the development of cognitive decline and neurodegenerative diseases, particularly
Alzheimer's disease. Our previous studies demonstrated that aging correlated with both morphological and
functional loss of meningeal lymphatic function, and that restoring meningeal lymphatic function in aging mice
improved cognitive decline and limited physiopathology in a mouse model of Alzheimer's disease. Transcriptomic
analysis of aged lymphatic endothelial cells revealed that interactions with the extracellular matrix and the
microenvironment may represent major factors in their age-associated loss of function. However, the molecular
mechanisms controlling the age-associated degeneration of the meningeal lymphatic remains unknown.
 Our preliminary data demonstrate that the integrin CD49a is expressed by lymphatic endothelial cells and
increases with aging. We generated a mouse where CD49a is deleted from lymphatic endothelial cells (LEC) (using
the Prox1creERT2 mice), and found that loss of CD49a by LEC improves their function. Furthermore, genome-wide
associated studies have identified CD49a as an associated gene with Alzheimer's disease. We found that global
CD49a-deficient mice have reduced amyloidosis pathology when crossed with a mouse model of Alzheimer's
disease. We therefore hypothesize that this age-associated increase in CD49a expression participates in their age-
associated functional decline, participates in the development of cognitive decline, and promotes the accumulation
of amyloid aggregates in Alzheimer's disease.
 Guided by our preliminary data, we propose to address our hypothesis using the following aims:
Aim 1: Determine the effects of CD49a in meningeal lymphatic function during aging.
Aim 2: Delineate how CD49a expression by LEC contributes to age-associated brain dysfunction.
 Collectively, our propose studies will have a significant impact by: a) revealing a molecular pathway
regulating age-associated meningeal lymphatic function, b) highlighting the importance of meningeal lymphatic
function in the maintenance of brain health during aging, and c) providing evidence for the therapeutic potential of
CD49a to manipulate meningeal lymphatic function in aging and neurodegeneration.

## Key facts

- **NIH application ID:** 10428808
- **Project number:** 1R21AG077370-01
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Antoine Louveau
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $442,750
- **Award type:** 1
- **Project period:** 2022-05-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428808

## Citation

> US National Institutes of Health, RePORTER application 10428808, Integrin mediated regulation of lymphatics during aging and neurodegeneration (1R21AG077370-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10428808. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*