Soluble TREM2 inhibits secondary nucleation of A13 fibrillization and enhances cellular uptake of fibrillar A13

Triggering receptor expressed on myeloid cells 2 (TREM2) is a single-pass transmembrane receptor of the immunoglobulin superfamily that is secreted in a soluble (sTREM2) form. Mutations in TREM2 have been linked to increased risk of Alzheimer's disease (AD). A prominent neuropathological component of AD is deposition of the amyloid-13 (A13) into plaques, particularly A1340 and A1342. While the membrane-bound form of TREM2 is known to facilitate uptake of A13 fibrils and the polarization of microglial processes toward amyloid plaques, the role of its soluble ectodomain, particularly in interactions with monomeric or fibrillar A13, has been less clear. Our results demonstrate that sTREM2 does not bind to monomeric A1340 and A1342, even at a high micromolar concentration, while it does bind to fibrillar A1342 and A1340 with equal affinities (2.6 +/- 0.3 pM and 2.3 +/- 0.4 pM). Kinetic analysis shows that sTREM2 inhibits the secondary nucleation step in the fibrillization of A13, while having little effect on the primary nucleation pathway. Furthermore, binding of sTREM2 to fibrils markedly enhanced uptake of fibrils into human microglial and neuroglioma derived cell lines. The disease-associated sTREM2 mutant, R47H, displayed little to no effect on fibril nucleation and binding, but it decreased uptake and functional responses markedly. We also probed the structure of the WT sTREM2-A13 fibril complex using integrative molecular modeling based primarily on the crosslinking mass spectrometry data. The model shows that sTREM2 binds fibrils along one face of the structure, leaving a second, mutation-sensitive site free to mediate cellular binding and uptake.

Automated summary

The soluble form of TREM2, sTREM2, was found to bind to fibrillar A1340 and A1342, enhancing their uptake into cells. sTREM2 inhibited the secondary nucleation step in A13 fibrillization, but had little effect on the primary nucleation pathway. The disease-associated mutant R47H showed reduced uptake and functional responses to fibrils. Molecular modeling revealed the binding mode of sTREM2 to A13 fibrils.