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.