High affinity interactions and signal transduction between Aβ oligomers and TREM2

Abstract

Rare coding variant in the Triggering receptor expressed on myeloid cells 2 (TREM2) are associated with increased risk for Alzheimers 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. We confirm the previous interaction between APOE3 and APOE4 and TREM2. 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 variant 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 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.