ArticleThe Journal of biological chemistry2013
Sequential proteolytic processing of the triggering receptor expressed on myeloid cells-2 (TREM2) protein by ectodomain shedding and γ-secretase-dependent intramembranous cleavage.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 200 papers, 2 of them syntheses that pooled it.
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Who cites it
200 citing papers in PubMed, 2 syntheses or guidelines pooled it, 297 citations in OpenAlex.
- Circulating and cerebrospinal fluid soluble TREM2 levels and risk of perioperative neurocognitive disorders in surgical patients: a systematic review and meta-analysis.Frontiers in aging neuroscience · 2026Pooled it
- Integrated genomic approaches identify major pathways and upstream regulators in late onset Alzheimer's disease.Scientific reports · 2015Pooled it
- Article
- Innate immune crosstalk in ALS/FTD pathogenesis.Cell insight · 2026Review
- CD33 and clusterin interact biophysically and genetically to modulate Alzheimer risk.Nature communications · 2026Article
- TREM2 in neurodegenerative diseases and acute neurological injuries: mechanisms to targeted therapies.Cell communication and signaling : CCS · 2026Review
- The Microglial Protein sTREM2 Inhibits the Bacterial Functional Amyloid CsgA and Suppresses Amyloid-Dependent Biofilm Formation.bioRxiv : the preprint server for biology · 2026Article
- Article
- Soluble TREM2 Is Elevated in Pediatric Patients with Anti-NMDAR Encephalitis.Journal of clinical medicine · 2026Article
- Parkinson's disease: spatiotemporal regulation and therapeutic prospects of TREM2-mediated microglial responses.NPJ Parkinson's disease · 2026Review
- ADAM17 as a proteolytic rheostat linking inflammation, tissue repair, and failure of inflammatory resolution in liver injury and fibrosis.Frontiers in pharmacology · 2026Review
- TREM2 and microglial immunity in Alzheimer's disease: mechanisms, genetics, and therapeutic opportunities.Frontiers in immunology · 2026Review
- TREM2-expressing macrophages in liver diseases.Trends in endocrinology and metabolism: TEM · 2026Review
- TREM2 as a central immunometabolic hub in Alzheimer's disease: linking microglial states, lipid stress, and disease-stage-specific intervention.Frontiers in immunology · 2026Review
- TREM2-mediated regulation of myeloid cells in the tumor microenvironment: new insights and therapeutic prospects.NPJ precision oncology · 2025Review
- Roles of TREM2 in Alzheimer's disease.Translational neurodegeneration · 2025Review
- Soluble CSF1R promotes microglial activation and amyloid clearance in alzheimer's disease.Journal of neuroinflammation · 2025Article
- Presenilin 1 E280A mutation induces dysfunctional astrocytic phenotype in menstrual stromal-derived astrocyte-like cells.Cellular and molecular life sciences : CMLS · 2025Article
- Synaptic dysfunction and glial activation markers throughout aging and early neurodegeneration: a longitudinal CSF biomarker-based study.Molecular neurodegeneration · 2025Article
- Is TREM2 a Stretch: Implications of TREM2 Along Spinal Cord Circuits in Health, Aging, Injury, and Disease.Cells · 2025Review
140 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Triggering receptor expressed on myeloid cells-2 (TREM2) and its signaling adaptor protein TYROBP/DAP12 play important roles in signal transduction in dendritic cells, osteoclasts, tissue macrophages, and microglia. Recently, TREM2 variants have been shown to be linked to late onset Alzheimer disease. Here, we demonstrate that TREM2 undergoes sequential proteolytic processing by ectodomain shedding and intramembrane proteolysis. The C-terminal fragment (CTF) of TREM2 generated by ectodomain shedding is cleaved by γ-secretase. Importantly, pharmacologic and genetic γ-secretase inhibition resulted in accumulation of TREM2 CTF at the plasma membrane that also interacts with the signaling adaptor protein DAP12. Thus, the accumulated TREM2 CTF thereby might limit the interaction of DAP12 with the functional full-length receptor, resulting in decreased DAP12 phosphorylation and impaired metabolism of phosphatidylinositol 4,5-bisphosphate. Together, these data demonstrate γ-secretase-mediated intramembranous proteolysis of TREM2 and functionally link two Alzheimer disease-associated proteins in one signaling pathway.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.