Functional insights from biophysical study of TREM2 interactions with ApoE and Aβ1-42

INTRODUCTION: TREM2 is an innate immune receptor expressed on myeloid cells including microglia in the brain. How TREM2 engages different ligands remains poorly understood. METHODS: We used comprehensive BLI analysis to investigate the TREM2 interactions with ApoE and amyloid beta 42. RESULTS: TREM2 binding did not depend on ApoE lipidation, and there were only slight differences in affinity observed between ApoE isoforms (E4 > E3 > E2). Surprisingly, disease-linked TREM2 variants within a "basic patch" minimally impact ApoE binding. Instead, TREM2 has a unique hydrophobic surface that can bind to ApoE. This direct engagement requires the major hinge region of ApoE. TREM2 directly binds monomeric amyloid beta 42 and can potently inhibit amyloid beta 42 polymerization, suggesting a potential mechanism for soluble TREM2 (sTREM2) in preventing AD pathogenesis. DISCUSSION: These findings demonstrate that TREM2 has at least two separate surfaces to engage ligands and uncovers a potential function for sTREM2 in directly binding and inhibiting amyloid beta polymerization.