Functional insights from biophysical study of TREM2 interactions with ApoE and Aβ_1-42

Abstract

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 monomeric amyloid beta (mAβ42). 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, diseaselinked 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 mAβ42 and can potently inhibit Aβ42 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 inhibiting Aβ polymerization.

Wild-type sTREM2 blocks Aβ aggregation and neurotoxicity, but the Alzheimer's R47H mutant increases Aβ aggregation

“…Crucially, however, we also found that wild-type sTREM2 inhibits the formation of fibrils and larger Aβ oligomers and disaggregates protofibrils and larger Aβ oligomers into the smallest Aβ oligomers. This is consistent with a recent, preliminary report ( 30 ) that WT sTREM2 inhibited Aβ aggregation, measured by thioflavin T assay. In contrast, we found that R47H sTREM2 promoted the formation of Aβ protofibrils, indicating a gain of function by this mutation.…”

Inflammatory Cascade in Alzheimer’s Disease Pathogenesis: A Review of Experimental Findings

“…TREM2 polymorphism causes structural changes in the receptor, leading to a partial loss of its function. However, the role of TREM2 in neurodegeneration and AD remains unclear [107].…”

APOEe4.Trem2*R47H Mice Show Changes in Alzheimer’s Disease-Relevant Processes in the Absence of Amyloid Plaques

“…Amyloid plaque formation is a primary diagnostic measure of Alzheimer's disease with both APOE and TREM2 linked to amyloid deposition (2,4,9,40,48,67,70,71). For example, TREM2 can bind amyloid, altering microglial function, linking the TREM2-APOE pathway directly to amyloid-driven disease progression (72,73). Loss of functional Trem2 in mice resulted in plaques that contained reduced amounts of APOE and promoted amyloidogenesis in mice by reducing microglial function (71,74) indicating that microglia, through TREM2 mediated signaling, can regulate APOE co-deposition around amyloid deposits.…”