Journal Article

High‐affinity interactions and signal transduction between Aβ oligomers and TREM2

Chakrabaty, Paramita, Lessard, Christian B, Colonna, Marco, Ulrich, Jason D, Malnik, Samuel L, Ladd, Thomas B, Mahan, Thomas E, Holtzman, David M, Zhou, Yingyue, Cruz, Pedro E, Ran, Yong, Golde, Todd E

2018

Overview

Rare coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with increased risk for Alzheimer's disease (AD), but how they confer this risk remains uncertain. We assessed binding of TREM2, AD‐associated TREM2 variants to various forms of Aβ and APOE in multiple assays. TREM2 interacts directly with various forms of Aβ, with highest affinity interactions observed between TREM2 and soluble Aβ42 oligomers. High‐affinity binding of TREM2 to Aβ oligomers is characterized by very slow dissociation. Pre‐incubation with Aβ is shown to block the interaction of APOE. In cellular assays, AD‐associated variants of TREM2 reduced the amount of Aβ42 internalized, and in NFAT assay, the R47H and R62H variants decreased NFAT signaling activity in response to Aβ42. These studies demonstrate i) a high‐affinity interaction between TREM2 and Aβ oligomers that can block interaction with another TREM2 ligand and ii) that AD‐associated TREM2 variants bind Aβ with equivalent affinity but show loss of function in terms of signaling and Aβ internalization. Synopsis Rare coding variants of TREM2 (R47H, R62H) are associated with increased risk for Alzheimer's disease (AD), but how they confer this risk remains uncertain. Using BioLayer Interferometry and other biochemical methods, TREM2 and AD‐associated variants binding to Aβ and APOE is examined. High‐affinity binding of TREM2 to Aβ oligomers is characterized by very slow dissociation which is almost “irreversible”. Pre‐incubation of TREM2 with Aβ oligomers is shown to block its interaction with APOE. AD‐associated TREM2 variants bound Aβ with equivalent affinity. AD‐associated TREM2 variants reduced Aβ42 internalization and NFAT signaling activity. AD‐associated TREM2 variants showed a partial loss of function. Graphical Abstract Rare coding variants of TREM2 (R47H, R62H) are associated with increased risk for Alzheimer's disease (AD), but how they confer this risk remains uncertain. Using BioLayer Interferometry and other biochemical methods, TREM2 and AD‐associated variants binding to Aβ and APOE is examined.

• Publisher: Nature Publishing Group UK,John Wiley and Sons Inc,Springer Nature
• Subject: Alzheimer's disease / amyloid / APOE / EMBO16 / EMBO27 / innate immune response / Research Article / TREM2