Open AccessAn Alzheimer‐associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function
Author(s) -
Schlepckow Kai,
Kleinberger Gernot,
Fukumori Akio,
Feederle Regina,
Lichtenthaler Stefan F,
Steiner Harald,
Haass Christian
Publication year - 2017
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.201707672
Subject(s) - trem2 , microbiology and biotechnology , cleavage (geology) , phagocytosis , function (biology) , chemistry , biology , immunology , microglia , inflammation , paleontology , fracture (geology)
Sequence variations occurring in the gene encoding the triggering receptor expressed on myeloid cells 2 ( TREM 2) support an essential function of microglia and innate immunity in the pathogenesis of Alzheimer's disease ( AD ) and other neurodegenerative disorders. TREM 2 matures within the secretory pathway, and its ectodomain is shed on the plasma membrane. Missense mutations in the immunoglobulin (Ig)‐like domain such as p.T66M and p.Y38C retain TREM 2 within the endoplasmic reticulum and reduce shedding as well as TREM 2‐dependent phagocytosis. Using mass spectrometry, we have now determined the cleavage site of TREM 2. TREM 2 is shed by proteases of the ADAM (a disintegrin and metalloproteinase domain containing protein) family C‐terminal to histidine 157, a position where an AD ‐associated coding variant has been discovered (p.H157Y) in the Han Chinese population. Opposite to the characterized mutations within the Ig‐like domain, such as p.T66M and p.Y38C, the p.H157Y variant within the stalk region leads to enhanced shedding of TREM 2. Elevated ectodomain shedding reduces cell surface full‐length TREM 2 and lowers TREM 2‐dependent phagocytosis. Therefore, two seemingly opposite cellular effects of TREM 2 variants, namely reduced versus enhanced shedding, result in similar phenotypic outcomes by reducing cell surface TREM 2.