RESUMO
Rare coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with increased risk for Alzheimer's disease (AD), but how they confer this risk remains uncertain. We assessed binding of TREM2, AD-associated TREM2 variants to various forms of Aß and APOE in multiple assays. TREM2 interacts directly with various forms of Aß, with highest affinity interactions observed between TREM2 and soluble Aß42 oligomers. High-affinity binding of TREM2 to Aß oligomers is characterized by very slow dissociation. Pre-incubation with Aß is shown to block the interaction of APOE In cellular assays, AD-associated variants of TREM2 reduced the amount of Aß42 internalized, and in NFAT assay, the R47H and R62H variants decreased NFAT signaling activity in response to Aß42. These studies demonstrate i) a high-affinity interaction between TREM2 and Aß oligomers that can block interaction with another TREM2 ligand and ii) that AD-associated TREM2 variants bind Aß with equivalent affinity but show loss of function in terms of signaling and Aß internalization.
