TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer’s disease-associated H157Y variant
Authors
Thornton, P
Sevalle, J
Fraser, G
Zhou, Y
Ståhl, S
Franssen, EH
Qamar, Seema
Gomez Perez-Nievas, B
Nicol, LSC
Eketjäll, S
Revell, J
Jones, C
Billington, A
Chessell, I
Crowther, D
Publication Date
2017-09-01Journal Title
EMBO Molecular Medicine
ISSN
1757-4676
Publisher
Wiley
Volume
9
Issue
9
Pages
1179-1326
Language
English
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Thornton, P., Sevalle, J., Deery, M., Fraser, G., Zhou, Y., Ståhl, S., Franssen, E., et al. (2017). TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer’s disease-associated H157Y variant. EMBO Molecular Medicine, 9 (9), 1179-1326. https://doi.org/10.15252/emmm.201707673
Abstract
We have characterised the proteolytic cleavage events responsible for
the shedding of Triggering Receptor Expressed on Myeloid cells 2
(TREM2) from primary cultures of human macrophages, murine
microglia and TREM2-expressing human embryonic kidney (HEK293)
cells. In all cell types, a soluble 17 kDa N-terminal cleavage fragment
was shed into the conditioned media in a constitutive process that is
inhibited by G1254023X and metalloprotease inhibitors and siRNA
targeting ADAM10. Inhibitors of serine proteases and matrix
metalloproteinases 2/9, and ADAM17 siRNA did not block TREM2
shedding. Peptidomimetic protease inhibitors highlighted a possible
cleavage site and mass spectrometry confirmed that shedding
occurred predominantly at the H157-S158 peptide bond for both wild
type and H157Y human TREM2 and for the wild type murine
orthologue. Crucially, we also show that the Alzheimer diseaseassociated
H157Y TREM2 variant was shed more rapidly than wild
type from HEK293 cells, possibly by a novel, batimastat- and
ADAM10-siRNA-independent, sheddase activity. These insights offer
new therapeutic targets for modulating the innate immune response
in Alzheimer’s and other neurological diseases.
Keywords
genetic risk, microglia, neurodegeneration, neuroinflammation
Sponsorship
Funding from the Wellcome Trust and the Canadian Institutes of Health Research contributed to the support of this study.
Funder references
MRC (MC_G1000734)
Wellcome Trust (203249/Z/16/Z)
MRC (MR/N012453/1)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.15252/emmm.201707673
This record's URL: https://www.repository.cam.ac.uk/handle/1810/267393
Rights
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International