Abstract (Expand)
The cell surface receptor TREM2 is a key genetic risk factor and drug target in Alzheimer's disease (AD). In the brain, TREM2 is expressed in microglia, where it undergoes proteolytic cleavage, … linked to AD risk, but the responsible protease in microglia is still unknown. Another microglial-expressed AD risk factor is catalytically inactive rhomboid 2 (iRhom2, RHBDF2), which binds to and acts as a non-catalytic subunit of the metalloprotease ADAM17. A potential role in TREM2 proteolysis is not yet known. Using microglial-like BV2 cells, bone marrow-derived macrophages, and primary murine microglia, we identify iRhom2 as a modifier of ADAM17-mediated TREM2 shedding. Loss of iRhom2 increased TREM2 in cell lysates and at the cell surface and enhanced TREM2 signaling and microglial phagocytosis of the amyloid β-peptide (Aβ). This study establishes ADAM17 as a physiological TREM2 protease in microglia and suggests iRhom2 as a potential drug target for modulating TREM2 proteolysis in AD.
Authors: Georg Jocher, Gozde Ozcelik, Stephan A Müller, Hung-En Hsia, Miranda Lastra Osua, Laura I Hofmann, Marlene Aßfalg, Lina Dinkel, Xiao Feng, Kai Schlepckow, Michael Willem, Christian Haass, Sabina Tahirovic, Carl P Blobel, Stefan F Lichtenthaler
Date Published: 13th Mar 2025
Publication Type: Journal
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