ArticleLife science alliance2025
The late-onset Alzheimer's disease risk factor RHBDF2 is a modifier of microglial TREM2 proteolysis.
Article in Life science alliance, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Nutritional substrates and microglial metabolic fitness in brain aging and Alzheimer's disease: from lipid handling to TREM2-linked translation.Frontiers in nutrition · 2026Review
- Article
- Roles of TREM2 in Alzheimer's disease.Translational neurodegeneration · 2025Review
- The immune response within Alzheimer's disease: from the lense of peripheral monocyte-derived macrophages.Journal of neuroimmunology · 2025Review
- RHBDF2 governs microglial neuroinflammation during cerebral ischemia-reperfusion injury and is positively regulated by the m6A reader YTHDF1.Molecular medicine (Cambridge, Mass.) · 2025Article
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Authors and funding
15 authors.
Funding
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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Registered trials
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