Abstract

Alzheimer’s disease is the most common cause of dementia, but scientists still do not understand why some people with age-related changes in the brain develop memory loss while others do not. Many older adults have amyloid plaques, one of the hallmark features of Alzheimer’s disease, yet remain cognitively healthy. In others, these plaques are followed by the buildup and spread of another protein called tau, which damages brain cells and leads to dementia. Understanding what drives this transition is a critical challenge in Alzheimer’s research.

Our research focuses on microglia, the brain’s immune cells, which are among the first cells to respond to amyloid plaques. We recently discovered that microglia produce a protein called Glypican-4 (GPC4) in response to amyloid. Our findings suggest that GPC4 may help tau spread between brain cells and interfere with the cells’ ability to remove harmful proteins, potentially accelerating Alzheimer’s disease.

This project will determine how amyloid activates microglia to produce GPC4, test whether blocking GPC4 can slow disease progression, and uncover how GPC4 disrupts normal brain cell function. By identifying a key biological link between amyloid plaques and tau pathology, this work could reveal new opportunities to prevent or slow Alzheimer’s disease before irreversible brain damage occurs.