High-affinity interactions and signal transduction between A beta oligomers and TREM2

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 A beta and APOE in multiple assays. TREM2 interacts directly with various forms of A beta, with highest affinity interactions observed between TREM2 and soluble A beta 42 oligomers. High-affinity binding of TREM2 to A beta oligomers is characterized by very slow dissociation. Pre-incubation with A beta is shown to block the interaction of APOE. In cellular assays, AD-associated variants of TREM2 reduced the amount of A beta 42 internalized, and in NFAT assay, the R47H and R62H variants decreased NFAT signaling activity in response to A beta 42. These studies demonstrate i) a high-affinity interaction between TREM2 and A beta oligomers that can block interaction with another TREM2 ligand and ii) that AD-associated TREM2 variants bind A beta with equivalent affinity but show loss of function in terms of signaling and A beta internalization.