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

TREM2 is a pattern recognition receptor, expressed on microglia and myeloid cells, detecting lipids and A beta and inducing an innate immune response. Missense mutations (e.g., R47H) of TREM2 increase risk of Alzheimer's disease (AD). The soluble ectodomain of wild-type TREM2 (sTREM2) has been shown to protect against AD in vivo, but the underlying mechanisms are unclear. We show that A beta oligomers bind to cellular TREM2, inducing shedding of the sTREM2 domain. Wild-type sTREM2 bound to A beta oligomers (measured by single-molecule imaging, dot blots, and Bio-Layer Interferometry) inhibited A beta oligomerization and disaggregated preformed A beta oligomers and protofibrils (measured by transmission electron microscopy, dot blots, and size-exclusion chromatography). Wild-type sTREM2 also inhibited A beta fibrillization (measured by imaging and thioflavin T fluorescence) and blocked A beta-induced neurotoxicity (measured by permeabilization of artificial membranes and by loss of neurons in primary neuronal-glial cocultures). In contrast, the R47H AD-risk variant of sTREM2 is less able to bind and disaggregate oligomeric A beta but rather promotes A beta protofibril formation and neurotoxicity. Thus, in addition to inducing an immune response, wild-type TREM2 may protect against amyloid pathology by the A beta-induced release of sTREM2, which blocks A beta aggregation and neurotoxicity. In contrast, R47H sTREM2 promotes A beta aggregation into protofibril that may be toxic to neurons. These findings may explain how wild-type sTREM2 apparently protects against AD in vivo and why a single copy of the R47H variant gene is associated with increased AD risk.