High affinity interactions and signal transduction between Aβ oligomers and TREM2

Lessard, C. B.; Malnik, S. L.; Zhou, Y.; Ladd, T. B.; Cruz, P. E.; Ran, Y.; Chakrabaty, P.; Mahan, T. E.; Holtzman, D. M.; Ulrich, J. D.; Colonna, M.; Golde, T.

doi:10.1101/269787

bioRxiv · 10.1101/269787

High affinity interactions and signal transduction between Aβ oligomers and TREM2

Lessard, C. B.·Malnik, S. L.·Zhou, Y.·Ladd, T. B.·Cruz, P. E.·Ran, Y.·Chakrabaty, P.·Mahan, T. E.·Holtzman, D. M.·Ulrich, J. D.·Colonna, M.·Golde, T.

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Abstract

Rare coding variant in the Triggering receptor expressed on myeloid cells 2 (TREM2) are associated with increased risk for Alzheimers disease (AD), but how they confer this risk remains uncertain. We assessed binding of TREM2, AD associated TREM2 variants to various forms of A{beta} and APOE in multiple assays. TREM2 interacts directly with various forms of A{beta}, with highest affinity interactions observed between TREM2 and soluble A{beta}42 oligomers. We confirm the previous interaction between APOE3 and APOE4 and TREM2. High affinity binding of TREM2 to A{beta} oligomers is characterized by very slow dissociation. Pre-incubation with A{beta} is shown to block the interaction of APOE. In cellular assays, AD-associated variants of TREM2 reduced the amount of A{beta}42 internalized, and in NFAT assay the R47H variant decreased NFAT signaling activity in response to A{beta}42. These studies demonstrate i) a high affinity interaction between TREM2 and A{beta} oligomers that can block interaction with another ligand and ii) that AD-associated TREM2 variants bind A{beta} with equivalent affinity but show loss of function in terms of signaling and A{beta} internalization.

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Lessard, C. B., Malnik, S. L., Zhou, Y., Ladd, T. B., Cruz, P. E., Ran, Y., Chakrabaty, P., Mahan, T. E., Holtzman, D. M., Ulrich, J. D., Colonna, M., Golde, T.. 2018-02-22. High affinity interactions and signal transduction between Aβ oligomers and TREM2. https://doi.org/10.1101/269787

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