The Astrocyte Cell Surface Proteome in Alzheimer’s Disease

This project aims to uncover how astrocyte cell surface protein landscape changes during Abeta accumulation in Alzheimer’s disease.

Cell surface proteins (CSPs) help cells communicate and respond to their environment, making them key drug targets. We performed CSP profiling of mouse astrocytes during Aß-amyloid plaque buildup and identified CD44 as a top candidate. We found that when CD44 binds to its ligand OPN, astrocytes trigger lipid accumulation, while mice lacking CD44 show reduced inflammation. By studying CD44 in live mice and cultured astrocytes, we aim to uncover its role in Alzheimer’s disease and explore its potential as a therapeutic target.

We pioneer the use of a novel in-situ cell surface proteomics method, employing a mouse line expressing a membrane-bound HRP in astrocytes coupled with TMT-MS profiling, to uncover the CSP landscape in response to Aß pathology. The conditional Cd44-floxed mice allow us to study the role of CD44 in astrocytes of adult mouse brains in Alzheimer’s disease pathogenesis. By integrating lipidomics and RNA-seq, we reveal how OPN-CD44 signaling regulates lipid metabolism and inflammation. CRISPRi screening identifies genetic modifiers of these phenotypes, offering insight into astrocyte-driven mechanisms in Alzheimer’s.

By generating an Alzheimer’s-associated astrocyte surface proteome dataset from mouse brains, we provide valuable information to the Alzheimer’s research community for in-depth mechanistic study and therapeutic exploration.

Our investigation into the OPN-CD44 axis in astrocyte-driven Alzheimer’s pathogenesis offers novel insights into how lipid metabolism and inflammation intersect in astrocytes. In addition, our in vivo analysis provides critical information regarding targeting CD44 as a potential therapy for Alzheimer’s.