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

Jan 27, 2022Proceedings of the National Academy of Sciences of the United States of America

Soluble TREM2 slows amyloid beta clumping and helps cells absorb amyloid beta fibers

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Abstract

binds to fibrillar Aβ40 and Aβ42 with affinities of 2.6 ± 0.3 µM and 2.3 ± 0.4 µM, respectively.

sTREM2 does not bind to monomeric Aβ40 and Aβ42 at high micromolar concentrations.
Kinetic analysis indicates that sTREM2 inhibits the secondary nucleation step in the formation of .
Binding of sTREM2 to fibrils enhances their uptake into human microglial and neuroglioma-derived cell lines.
The R47H mutation of sTREM2 shows little to no effect on fibril nucleation and binding, but significantly reduces uptake and functional responses.
Modeling suggests that sTREM2 binds to one face of the fibril structure, leaving another site available for cellular interaction.

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Triggering receptor expressed on myeloid cells 2 (TREM2) is a single-pass transmembrane receptor of the immunoglobulin superfamily that is secreted in a soluble () 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-β (Aβ) into plaques, particularly Aβ40 and Aβ42. While the membrane-bound form of TREM2 is known to facilitate uptake of and the polarization of microglial processes toward amyloid plaques, the role of its soluble ectodomain, particularly in interactions with monomeric or fibrillar Aβ, has been less clear. Our results demonstrate that sTREM2 does not bind to monomeric Aβ40 and Aβ42, even at a high micromolar concentration, while it does bind to fibrillar Aβ42 and Aβ40 with equal affinities (2.6 ± 0.3 µM and 2.3 ± 0.4 µM). Kinetic analysis shows that sTREM2 inhibits the secondary nucleation step in the fibrillization of Aβ, 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-Aβ fibril complex using integrative molecular modeling based primarily on the cross-linking 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.

Key numbers

2.6 ± 0.3 µM

Binding Affinity to Aβ42 Fibrils

binds to fibrillar Aβ42 with an apparent dissociation constant.

2.3 ± 0.4 µM

Binding Affinity to Aβ40 Fibrils

binds to fibrillar Aβ40 with an apparent dissociation constant.

approximately fourfold

Uptake Reduction by R47H Mutation

The R47H variant shows decreased uptake of compared to WT .

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

Abstract

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