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

INTRODUCTIONTREM2 is an innate immune receptor expressed on myeloid cells including microglia in the brain. How TREM2 engages different ligands remains poorly understood. METHODSWe used comprehensive BLI analysis to investigate the TREM2 interactions with ApoE and monomeric amyloid beta (mA{beta}42). RESULTSTREM2 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 hinge region of ApoE. TREM2 directly binds mA{beta}42 and can potently inhibit A{beta}42 polymerization, suggesting a potential mechanism for soluble TREM2 (sTREM2) in preventing AD pathogenesis. DISCUSSIONThese findings demonstrate that TREM2 has at least two separate surfaces to engage ligands and uncovers a potential function for sTREM2 in directly inhibiting A{beta} polymerization.