Investigating the Role of TREM2 T96K in Alzheimer’s Disease Pathogenesis

Project Summary

We aim to understand the role of the TREM2 T96K mutation in Alzheimer’s disease (AD) pathogenesis. In aim 1, we will investigate the effects of TREM2 T96K on amyloid-beta (Aß) pathology, neurodegeneration, and neuroinflammation in the 5xFAD mouse model of AD. In aim 2, we will assess the impact of the TREM2 T96K variant on the transcriptomic profile of microglia in the 5xFAD mice. In aim 3, we will use murine microglial BV2 cells and human iPSC-derived microglia-like cells carrying TREM2 T96K to uncover the molecular mechanisms underlying the impact of the TREM2 T96K mutation. 

We previously showed that the AD-associated T96K mutation in the ligand-binding domain of TREM2 markedly increased binding to TREM2 ligands and activation of TREM2, suggesting T96K is a gain-of-function mutation. While TREM2 loss-of-function mutations have been studied, no studies have yet been reported showing the effects of TREM2 gain-of-function mutations in mouse models of Alzheimer’s disease (AD). Using our novel Trem2 T96K knock-in (KI) mouse model crossed with the 5xFAD mice, we will investigate the functional consequences of the AD-associated TREM2 T96K mutation in vivo. The proposed study will provide critical insight into the role of the TREM2 T96K mutation in Alzheimer’s disease (AD), which may offer personalized AD treatment strategies depending on TREM2 genotype. In addition, our study will greatly extend our understanding of TREM2 functions in AD and facilitate the development of therapeutics targeting TREM2 and neuroinflammation for AD treatment.