TY  - JOUR
AU  - Jocher, Georg
AU  - Ozcelik, Gozde
AU  - Müller, Stephan A
AU  - Hsia, Hung-En
AU  - Lastra Osua, Miranda
AU  - Hofmann, Laura I
AU  - Aßfalg, Marlene
AU  - Dinkel, Lina
AU  - Feng, Xiao
AU  - Schlepckow, Kai
AU  - Willem, Michael
AU  - Haass, Christian
AU  - Tahirovic, Sabina
AU  - Blobel, Carl P
AU  - Lichtenthaler, Stefan F
TI  - The late-onset Alzheimer’s disease risk factor RHBDF2 is a modifier of microglial TREM2 proteolysis
JO  - Life science alliance
VL  - 8
IS  - 5
SN  - 2575-1077
CY  - Heidelberg
PB  - EMBO Press
M1  - DZNE-2025-00430
SP  - e202403080
PY  - 2025
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:40081988
DO  - DOI:10.26508/lsa.202403080
UR  - https://pub.dzne.de/record/277534
ER  -