The Role of TREM2 in AD Tauopathy

We are working to find new drug targets in the brain and to understand the biology of the newly identified immune molecule, triggering receptor expressed on myeloid cells 2, or TREM2, and its role in the Alzheimer’s disease (AD) tau pathology. There are a variety of different cell types in the brain, some of which are normally present, and some of which are recruited into the brain when it is diseased. We want to better understand the interactions of these cells and identify specific and unique therapeutic targets.

The TREM2 genetic variant has been shown to confer increased risk of developing late-onset AD (LOAD) and to elevated risk for other neurodegenerative diseases, including  frontotemporal dementia, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS).  However, virtually nothing is known regarding the role of TREM2 in tauopathy. Based upon recently published preliminary studies we hypothesize that TREM2 ablation will result in reduced inflammation within the brain, along with improved pathological outcomes, in a mouse model that develops protein aggregates (tau pathology) similar to those observed in human AD. In Aim 1, we will explore the role of TREM2 in modulating pathological outcomes in the hTau mouse model of AD tau pathology, focusing on effects on inflammation, neurodegeneration, and behavior. In Aim 2, we will characterize the impact of TREM2 deficiency on gene expression patterns within immune cells of the brain. There are a variety of different immune cell types in the brain, some of which are normally present, and some of which that are recruited into the brain when it is diseased. We want to better understand the interactions of these cells and identify specific and unique therapeutic targets that will impact Alzheimer’s disease brain pathologies.