BIOPHYSICAL INVESTIGATION OF THE TREM2 INTERACTIONS WITH APOE AND AMYLOID BETA1-42 REVEAL TWO DISTINCT BINDING SURFACES AND A POTENTIAL ROLE FOR STREM2 AS AN INHIBITOR OF AMYLOID BETA1-42 POLYMERIZATION

TREM2 is an innate immune receptor expressed on microglia that can also be proteolytically released in soluble form (sTREM2), and has rare variants that are potent risk factors for developing AD. A number of potential signaling ligands and binding partners for TREM2 have been identified, however, how TREM2 engages these different ligands remains poorly understood. We carried out comprehensive binding studies with biologically relevant forms of TREM2, ApoE, and amyloid beta (Ab) using BLI, and investigated the ability of sTREM2 to inhibit Ab1-42 self-polymerization. TREM2 directly binds unlipidated ApoE with mild isoform specificity through a mechanism that requires the hinge region of ApoE. Surprisingly, disease-linked TREM2 variants within a “basic patch” minimally impacted ApoE binding. Instead, we found that TREM2 utilizes on a unique hydrophobic surface to bind ApoE. We also found that TREM2 can also directly bind Ab1-42 monomers, and remarkably, sTREM2 inhibits Ab1-42 self-polymerization, suggesting an important role during AD pathogenesis. These findings demonstrate that TREM2 uses at least two separate surfaces to engage ligands, highlighting ways that TREM2 could be targeted to selectively enhance or disrupt specific interactions. In addition, we found that sTREM2 binds Ab1-42 monomers and inhibits their self-polymerization, identifying another potential role for TREM2 in AD development.