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EMBO Mol Med. 2017 Oct;9(10):1366-1378. doi: 10.15252/emmm.201707673.

TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer's disease-associated H157Y variant.

Author information

1
Neuroscience, Innovative Medicines and Early Development, AstraZeneca Granta Park, Cambridge, UK.
2
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada.
3
Cambridge Centre for Proteomics, University of Cambridge, Cambridge, UK.
4
AstraZeneca Translational Sciences Centre, Karolinska Institutet, Stockholm, Sweden.
5
Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
6
MedImmune Limited Granta Park, Cambridge, UK.
7
Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development, AstraZeneca, ICMC, Huddinge, Sweden.
8
Neuroscience, Innovative Medicines and Early Development, AstraZeneca Granta Park, Cambridge, UK damian.crowther@azneuro.com.

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's disease-associated 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

PMID:
28855301
PMCID:
PMC5623839
DOI:
10.15252/emmm.201707673
[Indexed for MEDLINE]
Free PMC Article

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