2023 Alzheimer's Association Research Grant (AARG)

Targeting microglial ADGRG/GPR56 to prevent Alzheimer’s disease progression

Does overexpression of a key microglial gene help prevent the progression of Alzheimer’s?

Xianhua Piao, Ph.D.
University of California
San Francisco, CA - United States

Background

Microglia, the resident immune cell of the brain, play a pivotal role in the progression of Alzheimer’s. This includes reacting to and clearing the build up of beta-amyloid plaques, a hallmark brain change  found in Alzheimer’s. In order to properly respond to plaques, microglia rely on a variety of proteins along their exterior called receptors. When activated, these receptors can signal within the cell and cause significant changes in its function and activity. One of these receptors is called GPR56.

Dr. Piao and colleagues previously showed reducing the amount of GPR56 present on microglia can lead to significantly more plaques in the brains of genetically-engineered Alzheimer's-like mice. Further, they showed that there were fewer microglia around the plaques. Having shown this, Piao and colleagues are now seeking to do the reverse: limit the number of plaques by increasing the amount of GPR56 in the microglia and expand their understanding to another hallmark brain change in Alzheimer’s, tau tangles.  .Tau tangles are the other classic protein found built up in Alzheimer’s. These tangles are found in nerve cells, the primary cell type in the brain, and can cause damage and, eventually, brain cell death. This failure of nerve cells is what leads to the cognitive issues seen in Alzheimer’s.

Research Plan

Dr. Piao’s and team have developed a mouse model that over expresses GPR56 specifically in microglia. They plan to use this model to look at how the overexpression changes the number of plaques, tangles, and microglia, and the relationship between them. Further, they plan to look at the health of nerve cells and  test simple cognitive function in these mice at 6 and 12 months which are the times that the mice without extra GPR56 show a decline in the cognitive function . Finally, they will look at what other proteins are affected by the increase in GPR56. These receptors can often trigger a wide range of changes in cells, so determining the extent of the changes can inform future experiments and reveal new targets that might help in the understanding of Alzheimer’s.

Impact

This project has the potential to confirm the importance of GPR56 in microglia interactions with amyloid plaques. It has the further potential to identify a target for potential drug development that could help slow the progression of Alzheimer’s.