2023 Endolysosomal Activity in Alzheimer’s (E2A)
Studying the role of microglia-specific endolysosomal dysfunction in AD
Which Alzheimer’s risk factors play a role in nutrient transport within brain cells?
Bart de Strooper, M.D., Ph.D.
Flemish Institute for Biotechnology
Leuven, Belgium
Background
Brain cells take up and transport nutrients, small molecules, and proteins through a process called “endocytosis” where material is packaged into “endosomes” which carry this material into the cell. Additionally, endosomes can carry cargo through the cell for removal by the brain’s waste disposal system. Endosomes are critical to the normal function of brain cells but become enlarged and abnormally accumulate in the brain in Alzheimer’s. Studies have shown that change in endosome function may be associated by the accumulation of beta amyloid plaques, one of the hallmark brain changes in Alzheimer’s. However, the mechanisms by which endocytosis becomes impaired in Alzheimer’s is unknown.
Research Plan
Dr. Bart de Strooper and colleagues will examine how three common genetic risk factors for Alzheimer’s are associated with changes in endosome function. To do this, they will use microglia, the brain’s primary immune cell, grown in a laboratory dish. First the researchers will use gene editing system called CRISPR to turn “off” the Alzheimer’s risk genes in microglia and measure how well the cells take up materials. They will also measure how well the cells use endocytosis to take up and remove beta amyloid plaques through the cell’s waste disposal system. Next, the team will identify which steps of the waste removal pathway are impaired by the common genetic risk factors for Alzheimer’s and may be responsible for beta amyloid plaque accumulation.
Impact
The results of this study may shed new light on how genetic risk factors for Alzheimer’s impair nutrient transport in brain cells. If successful, the findings could give rise to potential new therapeutic targets to prevent or slow down the hallmark brain changes in Alzheimer’s.