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2016 Grants - Xu
Promoting TREM2 Stability and Activity for Alzheimer’s Disease Intervention
Huaxi Xu, Ph.D.
Sanford-Burnham Medical Research Institute
La Jolla, CA
2016 Collaboration 4 Cure (C4C) Grant
Can new drug candidates that target the TREM2 protein on immune cells help regulate brain inflammation in Alzheimer’s disease?
The accumulation of beta-amyloid in the brain is a hallmark of Alzheimer’s disease. Researchers hypothesize that build-up of toxic beta-amyloid may trigger abnormal activation of immune cells in the brain called microglia. The overactivation of microglia can lead to high levels of inflammation and nerve cell damage. A protein called triggering receptor expressed on myeloid cells 2 (TREM2) is found on the surface of microglial cells in the brain is thought to be important for regulating inflammation and stimulating removal of damaged nerve cells. Certain variations in the TREM2 gene have been found to increase the risk of developing Alzheimer’s disease. While the exact role of TREM2 in Alzheimer’s disease is still under investigation, it is possible that promoting the stability or activity of TREM2 on immune cells could help modulate inflammation in the brain and preserve nerve cell function.
Dr. Huaxi Xu and colleagues have proposed studies to discover drug-like molecules that bind and stabilize TREM2. Drug-like molecules found to stabilize TREM2 would then be tested for their ability to inhibit the inflammatory response in microglial cells grown in a laboratory dish. The most promising candidates will be selected for future studies in animals to determine if the compounds can prevent or reduce Alzheimer’s-like brain changes.
The results of these studies may lead to the discovery of novel drug-like molecules that can stabilize and activate TREM2 on microglial cells. This work will help improve our understanding of TREM2’s role in Alzheimer’s and could lead to the future development of new treatments that may reduce or prevent inflammation in the brain during Alzheimer’s disease.