Wild-type sTREM2 blocks Aβ aggregation and neurotoxicity, while the Alzheimer’s R47H mutant does the opposite

Abstract

Missense mutations (e.g. R47H) of the microglial receptor TREM2 increase risk of Alzheimer’s disease (AD), and the soluble ectodomain of wild-type TREM2 (sTREM2) appears to protect in vivo, but the underlying mechanisms are unclear. We show that Aβ oligomers bind to TREM2, inducing shedding of sTREM2. Wild-type sTREM2 inhibits Aβ oligomerization, fibrillization and neurotoxicity, and disaggregates preformed Aβ oligomers and protofibrils. In contrast, the R47H AD-risk variant of sTREM2 is less able to bind and disaggregate oligomeric Aβ, but rather promotes Aβ protofibril formation and neurotoxicity. Thus, in addition to mediating phagocytosis, wild-type TREM2 may protect against amyloid pathology by Aβ-induced release of sTREM2 that blocks Aβ aggregation and neurotoxicity; while R47H sTREM2 promotes Aβ aggregation into neurotoxic forms, which may explain why the R47H variant gene increases AD risk several fold.

VEGF controls microglial phagocytic response to amyloid-β

“…The key question is now to understand how the VEGF-induced release of microglial sTREM2 could underlie the associated increase in Aβo phagocytosis. The high affinity binding of TREM2 ectodomain for Aβo and the slow dissociation kinetics of the complex (Lessard et al, 2018) could be instrumental in the blockade of Aβ aggregation, as it has been recently shown for a VEGF-derived peptide (Kober et al, 2020;Vilalta et al, 2021;Bouvet et al, 2023). Thus, the time-dependent effect of VEGF on microglial ADAM10/17 proteolytic activity may result in an early blockade of Aβ aggregation via sTREM2 release, followed by a subsequent TREM2-mediated increase in the phagocytosis of small oligomeric species.…”