TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer’s disease-associated H157Y variant
P. Thornton, J. Sevalle, M.J. Deery, G. Fraser, Y. Zhou, S. Ståhl, E.H. Franssen, R.B. Dodd, S. Qamar, B. Gomez Perez-Nievas, L.S.C. Nicol, S. Eketjäll, J. Revell, C. Jones, A. Billinton, P. St George-Hyslop, I. Chessell & D.C. Crowther
Sequence variation in the microglial receptor protein TREM2 is linked to risk for Alzheimer’s disease; one possible mechanism by which variants cause neurodegeneration is by impeding delivery, or reducing availability, of the protein to the cell surface. By contrast, the pathogenic role of proteolytic loss of TREM2 from the cell is unknown.
- TREM2 was shed rapidly from primary macrophages and microglia under basal conditions
- the sheddase site between positions 157&158 was identified using peptidomimetic inhibitors and mass spectrometry
- the Alzheimer's disease-linked H157Y TREM2 sheddase-cleavage-site variant was shed more rapidly than wild type
- for both wild type and variant TREM2 the major sheddase was ADAM10, however an additional proteolytic activity might be recruited by the H157Y variant
- the protection of TREM2 from proteolysis might represent a novel therapeutic approach