ArticleEMBO molecular medicine2020
Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region.
Article in EMBO molecular medicine, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 188 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
188 citing papers in PubMed, 1 synthesis or guideline pooled it, 349 citations in OpenAlex.
- Gain-of-function Modulation of TREM2 and its Impact on Amyloid-β and Tau Pathologies in Alzheimer's Disease: A Systematic Review and Meta-analysis of Animal Studies.Molecular neurobiology · 2026Pooled it
- The TREM2 agonistic antibody AL002 in early Alzheimer's disease: a phase 2 randomized trial.Nature medicine · 2026Trial
- Phase 1, First-In-Human, Single-/Multiple-Ascending Dose Study of Iluzanebart in Healthy Volunteers.Annals of clinical and translational neurology · 2025Trial
- Preclinical and first-in-human evaluation of AL002, a novel TREM2 agonistic antibody for Alzheimer's disease.Alzheimer's research & therapy · 2024Trial
- CD11c + microglia: From basic research to clinical application.Neural regeneration research · 2026Article
- Context-dependent TREM2 signalling in myeloid cells: Molecular mechanisms and immunotherapeutic divergence in neurodegeneration and cancer.Clinical and translational medicine · 2026Review
- Small-molecule TREM2 agonists: From artificial intelligence driven discovery to therapeutic application in Alzheimer's disease.Neural regeneration research · 2026Article
- Uncovering the biological mechanisms of TREM2 with molecular simulations: A comprehensive review and perspective.Progress in biophysics and molecular biology · 2026Review
- Microglial TDP-43 mediates myelin refinement and represses Tyrobp cryptic exon inclusion in mice.Nature neuroscience · 2026Article
- Targeting Mitochondrial Dysfunction in Microglia: A New Frontier for Treating Neurodegenerative Diseases.Molecular neurobiology · 2026Review
- TREM2-Targeting peptide tracer for neuroinflammation PET imaging.European journal of nuclear medicine and molecular imaging · 2026Article
- Neuroinflammation in Alzheimer's and Parkinson's diseases: pathogenic mechanisms and therapeutic strategies.Translational neurodegeneration · 2026Review
- TREM2 in neurodegenerative diseases and acute neurological injuries: mechanisms to targeted therapies.Cell communication and signaling : CCS · 2026Review
- Recent advances in Alzheimer's disease: From molecular mechanisms to therapeutic strategies.Cell · 2026Review
- Microglial checkpoint collapse in Alzheimer's disease: a tri-axial framework for biomarker-informed neuroimmune therapy.Journal of neuroinflammation · 2026Review
- Therapeutic targeting of neuroimmune mechanisms in neurodegeneration.Nature reviews. Drug discovery · 2026Review
- Triggering receptor expressed on myeloid cell family in atherosclerosis: from mechanisms to intervention strategies.Cell communication and signaling : CCS · 2026Review
- Interplay of oxidative stress and neuroinflammation in alzheimer's: insights into age-driven pathogenesis.Inflammopharmacology · 2026Review
- A ligand-mimetic anti-TREM2 agonist antibody elevates soluble TREM2 and ameliorates pathology in mouse models of Alzheimer's disease and multiple sclerosis.Journal of neuroinflammation · 2026Article
- Synthetic cleavage-resistant TREM2 boosts macrophage efferocytosis to treat inflammatory diseases.Cell reports. Medicine · 2026Article
128 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
28 authors at 3 institutions in 3 countries.
Funding
Abstract
Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a disease-associated microglial state. To enhance TREM2 activity, we sought to selectively increase the full-length protein on the cell surface via reducing its proteolytic shedding by A Disintegrin And Metalloproteinase (i.e., α-secretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for α-secretase-mediated shedding. Monoclonal antibody 4D9, which has a stalk region epitope close to the cleavage site, demonstrated dual mechanisms of action by stabilizing TREM2 on the cell surface and reducing its shedding, and concomitantly activating phospho-SYK signaling. 4D9 stimulated survival of macrophages and increased microglial uptake of myelin debris and amyloid β-peptide in vitro. In vivo target engagement was demonstrated in cerebrospinal fluid, where nearly all soluble TREM2 was 4D9-bound. Moreover, in a mouse model for Alzheimer's disease-related pathology, 4D9 reduced amyloidogenesis, enhanced microglial TREM2 expression, and reduced a homeostatic marker, suggesting a protective function by driving microglia toward a disease-associated state.
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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.