Abstract Body

Genetic variants nearby, and in some cases, rare missense mutations in a variety of genes expressed in microglia associated with either increased or decreased risk for late onset Alzheimer’s disease (AD). These AD-associated genes include the triggering receptor expressed in myeloid cells 2 (TREM2), phospholipase C gamma 2 (PLCG2), Abl Interactor member 3 (ABI3), MS4A4 amongst others. We show here that Aβ oligomers, but not Aβ monomers, bind to TREM2 with nanomolar affinity, and induce Aβ-dose-dependent shedding of TREM2 ectodomain, DAP12 and SYK phosphorylation. Similar effects are induced by anti-TREM2 antibodies. We propose that these intracellular signalling pathway changes activate protective microglial mechanisms, and the AD related variants affect these mechanisms. In addition, we show that the shed soluble sTREM also has protective effects, inhibiting Aβ oligomer formation, disrupting preformed Aβ oligomers and reducing Aβ-induced neurotoxicity. Crucially, R47H sTREM2 failed to disrupt Aβ oligomerization, and in fact encouraged larger more neurotoxic oligomers. sTREM2 and TREM2 signalling pathways represent potential therapeutic targets.