Journal Article

DZNE-2025-00430

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The late-onset Alzheimer’s disease risk factor RHBDF2 is a modifier of microglial TREM2 proteolysis

Jocher, G. (First author)DZNE* ; Ozcelik, G.DZNE* ; Müller, S. A.DZNE* ; Hsia, H.-E.DZNE* ; Lastra Osua, M.DZNE* ; Hofmann, L. I.DZNE* ; Aßfalg, M.DZNE* ; Dinkel, L.DZNE* ; Feng, X.DZNE* ; Schlepckow, K.DZNE* ; Willem, M. ; Haass, C.DZNE* ; Tahirovic, S.DZNE* ; Blobel, C. P. ; Lichtenthaler, S. F. (Last author)DZNE*

2025
EMBO Press Heidelberg

This record in other databases:    

Please use a persistent id in citations: doi:10.26508/lsa.202403080

Abstract: 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.

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Contributing Institute(s):

1. Neuroproteomics (AG Lichtenthaler)
2. Juvenile Neurodegeneration (AG Tahirovic)
3. Molecular Neurodegeneration (AG Haass)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2025

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Database coverage:
; ; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF < 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Dataset Müller, S. A.DZNE* ; Lichtenthaler, S.DZNE*
Dataset: Secretomics of ADAM17 and iRhom2 KO BV2 cells using high-performance secretome protein enrichment with click sugars
PRoteomics IDEntifications Database (2025)2025   Fulltext BibTeX | EndNote: XML, Text | RIS

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Dataset Müller, S. A.DZNE* ; Lichtenthaler, S.DZNE*
Dataset: Proteomics of ADAM17 and iRhom2 KO microglia using high-performance secretome protein enrichment with click sugars
PRoteomics IDEntifications Database (2025)2025   Fulltext BibTeX | EndNote: XML, Text | RIS

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