High affinity interactions and signal transduction between Aβ oligomers and TREM2

Rare coding variant 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 Aβ and APOE in multiple assays. TREM2 interacts directly with various forms of Aβ, with highest affinity interactions observed between TREM2 and soluble Aβ42 oligomers. We confirm the previous interaction between APOE3 and APOE4 and TREM2. High affinity binding of TREM2 to Aβ oligomers is characterized by very slow dissociation. Pre-incubation with Aβ is shown to block the interaction of APOE. In cellular assays, AD-associated variants of TREM2 reduced the amount of Aβ42 internalized, and in NFAT assay the R47H variant decreased NFAT signaling activity in response to Aβ42. These studies demonstrate i) a high affinity interaction between TREM2 and Aβ oligomers that can block interaction with another ligand and ii) that AD-associated TREM2 variants bind Aβ with equivalent affinity but show loss of function in terms of signaling and Aβ internalization.