Decipher the Astrocyte Cell-Surface Proteome in Alzheimer’s Disease

Astrocytes, the star-shaped cells, play essential roles in maintaining brain health. These cells provide energy and other nutrients to neurons. They are also in close contact with the blood-brain barrier to ensure its integrity. Astrocytes perform these duties by communicating with these cells via their cell surface proteins. In Alzheimer’s disease, the development of amyloid beta plaques and neurofibrillary tangles are accompanied by profound changes in astrocytes. They lose their normal star-like morphology and become enlarged and “inflamed.” We know that these involve changes of the expression of many genes; some are up, and others are down. However, how these lead to changes in cell surface proteins, which are the direct mediators of astrocyte function, are not well understood. Addressing this question is critically important to identify disease-associated proteins for therapeutic intervention that is the primary objective of this project. We will use a newly developed technique that can tag the astrocyte cell surface proteins in the brains of Alzheimer’s disease (AD) mouse models and identify these tagged proteins by mass spectrometry. We will then make a rank list of these proteins based on their inducibility by amyloid beta or neurofibrillary tangle pathologies observed in both mouse models and human AD patients and test their functions in human induced pluripotent stem cells. This study will discover novel therapeutic targets against Alzheimer’s disease and develop a cell surface proteome atlas, thus opening new research avenues for the AD research community.