ArticleFrontiers in cellular neuroscience2019
Distinct Signaling Pathways Regulate TREM2 Phagocytic and NFκB Antagonistic Activities.
Article in Frontiers in cellular neuroscience, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers, 1 of them a synthesis that pooled it.
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Who cites it
68 citing papers in PubMed, 1 synthesis or guideline pooled it, 107 citations in OpenAlex.
- Pooled it
- Uncovering the biological mechanisms of TREM2 with molecular simulations: A comprehensive review and perspective.Progress in biophysics and molecular biology · 2026Review
- TREM2 in neurodegenerative diseases and acute neurological injuries: mechanisms to targeted therapies.Cell communication and signaling : CCS · 2026Review
- The role of DAP12 in immune-related inflammatory diseases.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Review
- ADAR1 Controls Macrophage Scavenging and Lipid-Buffering Programs in Metabolic Tissues.European journal of immunology · 2026Article
- Sex Differences in Metabolite-Immune Circuits of Neuroinflammation.Immunological reviews · 2026Review
- Neuron-Derived Sema3B Facilitates Microglial Hematoma Clearance After Intracerebral Hemorrhage.Antioxidants (Basel, Switzerland) · 2026Article
- Microglial phagocytosis in epilepsy: Mechanisms and impact.The Journal of physiology · 2026Review
- Role of TREM2 in neuroinflammation regulation: mechanisms, disease associations, and therapeutic translation advances.Journal of translational medicine · 2025Review
- Roles of TREM2 in Alzheimer's disease.Translational neurodegeneration · 2025Review
- Chronic alcohol consumption induces phenotypic and functional alterations consistent with a hyper-inflammatory state in peripheral blood mononuclear cell-derived microglia in a rhesus macaque model.Brain, behavior, and immunity · 2025Article
- Article
- A PKCη missense mutation enhances Golgi-localized signaling and is associated with recessively inherited familial Alzheimer's disease.Science signaling · 2025Article
- Revisiting the critical roles of reactive microglia in traumatic brain injury.International journal of surgery (London, England) · 2025Review
- Protein kinase C eta enhances Golgi-localized signaling and is associated with Alzheimer's disease using a recessive mode of inheritance.medRxiv : the preprint server for health sciences · 2025Article
- Huang-Lian-Jie-Du decoction alleviates cognitive deficits in Alzheimer's disease model 5xFAD mice by inhibiting Trem2/Dap12 signaling pathway.Chinese medicine · 2025Article
- Synergistic reduction in interfacial flexibility of TREM2Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Microglia, Trem2, and Neurodegeneration.The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry · 2025Review
- Celastrol Ameliorated Alzheimer's Disease in Mice by Enhancing TBX21/TREM2 Expression in Microglia and Inhibiting Tau Phosphorylation.Neurochemical research · 2025Article
- Dehydroervatamine as a promising novel TREM2 agonist, attenuates neuroinflammation.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Article
8 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Several genetic variants of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) have been shown to increase the risk of developing Alzheimer's disease (AD) supporting a role of microglia and immune cells in the pathobiology of AD. We have employed an ectopic model of TREM2 and DAP12 expression in HEK293 cells to study selectively TREM2 dependent signaling and phagocytic functions and evaluated the effects of some of the TREM2 mutations associated with AD. We show that shedding of the TREM2 N-terminal domain does not affect the inhibition of NFκB activation induced by TREM2 while it completely blocks phagocytosis suggesting that TREM2 anti-inflammatory properties can be mediated by the TREM2 C-terminal fragment while the phagocytic activity requires the full-length receptor. In addition, we confirm in that model that apolipoprotein E (APOE) is a ligand for TREM2 and triggers TREM2 signaling. In particular, we show that APOE4 stimulates spleen tyrosine kinase (SYK) activation more potently than APOE2 in a TREM2 dependent manner. Interestingly, TREM2 appears to antagonize NFκB activation induced by phorbol ester but is unable to prevent TNFα induction of NFκB activation suggesting that TREM2 antagonizes inflammatory events triggered downstream of PKC. TREM2 mutations drastically impact TREM2 phagocytosis as well as its ability to antagonize NFκB activation and notably prevent the activation of the PI3K/AKT pathway observed with wild-type TREM2. Overall our data suggest that TREM2 dependent phagocytosis requires an activation of the SYK/PI3K/AKT/PLCγ pathways while the suppression of NFκB activation by TREM2 is independent of SYK, PI3K, and PLCγ activities. This model of ectopic TREM2-DAP12 co-expression appears suitable to study TREM2 signaling as several biological functions of TREM2 and TREM2 mutations that have been previously described in myeloid and microglial cells were also replicated in this model.
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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.