Thomas Brett, PhD, Associate Professor of Medicine, Associate Professor of Cell Biology and Physiology, Associate Professor of Biochemistry and Molecular Biophysics, WashU Medicine Division of Pulmonary & Critical Care Medicine, Jen Alexander-Brett, MD, PhD, Assistant Professor of Medicine, WashU Medicine Division of Pulmonary and Critical Care Medicine, Daisy Leung, PhD, Professor, Departments of Medicine, Pathology and Immunology, and Biochemistry and Molecular Biophysics, WashU Medicine Division of Infectious Diseases, along with postdoc David Price and WashU students: Jess Greven (lead author), Josh Wydra, Cynthia Zhi, Jordyn Svoboda, and Chris Camitta from Brett Lab were recently published in Molecular Neurodegeneration.
Alzheimer’s disease is highlighted by tangles of tau and amyloid beta plaques. Currently, the only therapeutics available for treating Alzheimer’s disease directly target amyloid beta plaques and their buildup. There is a dire need to develop new and innovative therapies for Alzheimer’s disease that target alternative pathways.
TREM2 is a protein that has recently become an important drug target for Alzheimer’s due to its engagement with proteins that cause microglia, critical immune cells in the brain, to carry out functions that can impact Alzheimer’s progression. Understanding how ligands engage TREM2 is one of the first steps to designing drugs that effectively target TREM2. New research from a team lead by Tom Brett and Jen Alexander-Brett in the Department of Medicine provides critical information in this regard.
This project represents a massive team effort to create the largest known protein library of TREM2 point mutants, which together, helped our group create a map of TREM2’s binding surfaces with AD-related proteins.
The team used this library to map interactions of TREM2 with 5 different proteins linked to Alzheimer’s, including apoliproteinE and amyloid beta. Their research revealed a common surface on TREM2 that engaged most of the studied ligands.
“Because TREM2 is implicated in so many disease pathways– Alzheimer’s, COPD, cancer– this project opens the door for a more robust understanding of receptor engagement and eventual intervention” said Jen Alexander-Brett, co-corresponding author on the study. “Our work here provides the most comprehensive information on which areas of TREM2 to target with drugs.” said Tom Brett, co-corresponding author. This work was recently published in Molecular Neurodegeneration.