2023 Alzheimer's Association Research Grant (AARG)
Exploring the SORL1-retromer axis as a novel therapeutic pathway in AD
Can the mechanism of transport within a cell provide new opportunities for drug development?
Jessica Young, Ph.D.
University of Washington
Seattle, WA - United States
Background
The endolysosomal system is a complex system responsible for sorting and breaking down unwanted materials in cells, including clearing abnormal tau from the brain. When problems in this system arise, they often do so because a group of proteins called the retromer can become impaired. The retromer is responsible for helping sort and move proteins throughout the cell to their correct destination. The endolysosomal system determines which substances are broken down and removed from the brain. When the retromer becomes impaired, however, the brain may lose its ability to dispose of unwanted proteins efficiently, which can lead to the build-up of disease-related molecules. In Alzheimer’s, dysfunction of this pathway is commonly observed and many genes in the network are associated with increased risk of Alzheimer’s.
Dr. Young and colleagues will investigate how this dysfunction occurs and how it affects two important cell types in the brain: nerve cells and microglia, which are the resident immune cells of the brain. An important gene in this pathway is SORL1, a multi-part sorting protein critical for proper network function.
Research Plan
Dr. Young will test how the reduction and removal of SORL1 affects the endolysosomal system in microglia and nerve cells. Additionally, they will use a drug that can enhance the endolysosomal system to see if it can reverse the effects of either reduction or removal of SORL1. By looking at these cell types, the team will be able to look at changes in their functions that have far ranging effects in Alzheimer’s.
Impact
This project has the potential to provide targets for drug development within the endolysosomal network, which could be very beneficial in Alzheimer’s treatment. These drugs have the somewhat unique potential to not just slow or prevent the pathology seen in Alzheimer’s but could actually help to reverse it.