Structural and functional analysis of TREM2 interactions with amyloid beta reveal molecular mechanisms that mediate phagocytosis of oligomeric amyloid beta

Abstract

AbstractThe TREM2 receptor is expressed on microglia in the brain, where it plays critical roles regulating microglia function. TREM2 engages a number of ligands involved in Alzheimer’s disease, and consequent signaling triggers phagocytosis, activation, survival, and proliferation. TREM2 has emerged as a drug target for AD, however very little is known regarding the structural basis for TREM2 microglial functions. Here we investigated the engagement of oligomeric amyloid beta (oAβ42) with TREM2. Using familial variants of amyloid beta, we show that mutations in the N-terminal portion of Aβ, notably residues H6 and D7, disrupt binding to TREM2. We then co-crystallized TREM2 with Aβ(1-8) peptide and determined the high resolution crystal structure. The structure revealed the peptide binds to the hydrophobic site of TREM2, closest to CDR1. Mutational and binding studies using BLI confirmed that mutations to the hydrophobic site ablate binding to oAβ42. Finally, we show that these interactions are critical to triggering phagocytosis of oAβ42, as oAβ42 variants H6R and D7N are not phagocytosed. Altogether, these data indicate that TREM2 engages oAβ42 using the hydrophobic site on TREM2 and the N-terminal portion of Aβ, and that this interaction is critical to trigger signaling and phagocytosis.