Open AccessHigh‐affinity interactions and signal transduction between Aβ oligomers and TREM 2
Author(s) -
Lessard Christian B,
Malnik Samuel L,
Zhou Yingyue,
Ladd Thomas B,
Cruz Pedro E,
Ran Yong,
Mahan Thomas E,
Chakrabaty Paramita,
Holtzman David M,
Ulrich Jason D,
Colonna Marco,
Golde Todd E
Publication year - 2018
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201809027
Subject(s) - signal transduction , chemistry , microbiology and biotechnology , biophysics , biochemistry , biology
Rare coding variants in the triggering receptor expressed on myeloid cells 2 ( TREM 2) are associated with increased risk for Alzheimer's disease ( AD ), but how they confer this risk remains uncertain. We assessed binding of TREM 2, AD ‐associated TREM 2 variants to various forms of Aβ and APOE in multiple assays. TREM 2 interacts directly with various forms of Aβ, with highest affinity interactions observed between TREM 2 and soluble Aβ42 oligomers. High‐affinity binding of TREM 2 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 TREM 2 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 TREM 2 and Aβ oligomers that can block interaction with another TREM 2 ligand and ii) that AD ‐associated TREM 2 variants bind Aβ with equivalent affinity but show loss of function in terms of signaling and Aβ internalization.