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Can targeting brain immune cells impact the accumulation of Alzheimer’s-related proteins in the brain as a treatment path?
Thomas Brett, Ph.D.
Washington University in St.Louis
St. Louis , MO - United States
Background
The immune system is complex and serves to maintain our overall health. Microglia are the primary immune cells in the brain and work to maintain healthy nerve cells by removing unwanted molecules in the brain, along with other functions. Increasing evidence suggests that communication between nerve cells and microglia becomes altered in Alzheimer’s, which may contribute to changes in brain function associated with the disease. Such alterations may be related to a protein on the surface of microglia called Triggering Receptor Expressed on Myeloid cells 2 (TREM2). Scientists believe this protein normally helps stimulate removal of unwanted molecules including beta-amyloid, a sticky protein fragment that forms abnormal clumps called plaques in the brain that are a key hallmark of Alzheimer’s. Certain variations in the TREM2 gene, however, may produce proteins that are unable to carry out helpful functions and instead increase one’s risk for developing Alzheimer’s. Yet the exact role of TREM2 in the disease is still under investigation.
Research Plan
Dr. Thomas Brett and colleagues will study how TREM2 interacts with beta-amyloid and work to identify potential drugs that modulate this interaction. The team has already screened drugs approved by the U.S. Food and Drug Administration for their ability to bind TREM2. They discovered existing antiviral drugs that enhance the binding of beta-amyloid to TREM2, increasing uptake and removal of beta-amyloid from the brain. The researchers believe that these drugs could potentially be used to treat Alzheimer’s by modulating TREM2 microglial function.
To investigate further, Dr. Thomas Brett and colleagues will study the structural details of how TREM2 interacts with beta-amyloid using human cells grown in laboratory dishes. The researchers will also study how Simepravir and Dasabuvir modulate the TREM2/beta-amyloid interaction and alter the function of TREM2.
Impact
This project may help clarify the role of microglia, and specifically the TREM2 protein, in limiting the accumulation of beta-amyloid plaques in the brain in Alzheimer’s. The results may identify how potential drug molecules modulate the interaction between TREM2 and beta-amyloid, which may provide new avenues of research for therapy development.
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