Therapeutic Modulation of TREM2 Activity

There is strong evidence that inflammation occurs in different stages of Alzheimer’s disease; understanding this process can help us to design new therapeutic approaches. TREM2 is a protein directly involved in the inflammation process that occurs in the brains of patients with Alzheimer’s disease. Mutations in the TREM2 protein increase the risk of developing Alzheimer’s disease up to threefold. A fragment of this protein, called soluble TREM2 (sTREM2), increases at the earliest stages of Alzheimer’s disease. This sTREM2 increase occurs in parallel to an increase in biomarkers signaling cell death in neurons. Our research demonstrates that increased sTREM2 indicates a protective response. The goal of this research is to maintain this protective response in later stages of Alzheimer’s disease by enhancing TREM2 activity. To accomplish this, we will look for a way to prevent the cleavage of TREM2, which would result in an increase in TREM2 levels on the surface of brain cells. The downstream effect of this increase will be to increase the clearance of amyloid beta plaques and cellular debris. Our research has identified the exact spot where this protein is cleaved. Of interest, there is a disease-causing mutation exactly at this site that occurs in Alzheimer’s disease patients. This mutation increases the cleavage of TREM2 and, as a consequence, reduces its function. Successful identification of the cleavage site will enable us to generate therapeutic antibodies to block the access of the enzyme that cleaves TREM2.