ArticleProceedings of the National Academy of Sciences of the United States of America2022
Soluble TREM2 inhibits secondary nucleation of Aβ fibrillization and enhances cellular uptake of fibrillar Aβ.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 82 citations in OpenAlex.
- Uncovering the biological mechanisms of TREM2 with molecular simulations: A comprehensive review and perspective.Progress in biophysics and molecular biology · 2026Review
- Recent advances in Alzheimer's disease: From molecular mechanisms to therapeutic strategies.Cell · 2026Review
- The Microglial Protein sTREM2 Inhibits the Bacterial Functional Amyloid CsgA and Suppresses Amyloid-Dependent Biofilm Formation.bioRxiv : the preprint server for biology · 2026Article
- TREM2 drives monocyte-derived macrophage responses tobioRxiv : the preprint server for biology · 2026Article
- XL-MS and De Novo Protein Design Identified a Common Motif for TREM2 Binding.bioRxiv : the preprint server for biology · 2026Article
- Parkinson's disease: spatiotemporal regulation and therapeutic prospects of TREM2-mediated microglial responses.NPJ Parkinson's disease · 2026Review
- Revisiting TREM2: from multi-omics signaling networks to clinical translation.Frontiers in immunology · 2026Review
- TREM2-directed therapy in Alzheimer's disease: from therapeutic window to clinical translation.Frontiers in aging neuroscience · 2026Review
- Inhibition of Acyl-CoenzymeA: Cholesterol Acyltransferase 1 promotes shedding of soluble triggering receptor on myeloid cells 2 (TREM2) and low-density lipoprotein receptor 1 (LRP1)-dependent phagocytosis of amyloid beta protein in microglia.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Midkine attenuates amyloid-β fibril assembly and plaque formation.Nature structural & molecular biology · 2025Article
- Roles of TREM2 in Alzheimer's disease.Translational neurodegeneration · 2025Review
- The flexible stalk domain of sTREM2 modulates its interactions with brain-based phospholipids.eLife · 2025Article
- Review
- Mutant THAP11 causes cerebellar neurodegeneration and triggers TREM2-mediated microglial activation in mice.The Journal of clinical investigation · 2025Article
- Unraveling the complex role of microglia in Alzheimer's disease: amyloid β metabolism and plaque formation.Inflammation and regeneration · 2025Review
- Microglia, Trem2, and Neurodegeneration.The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry · 2025Review
- TREM2 Deficiency Regulates Macrophage Apoptosis and Repair in Radiation-Induced Skin Injury.Research (Washington, D.C.) · 2025Article
- Biochemical and biophysical mechanisms macrophages use to tune phagocytic appetite.Journal of cell science · 2025Review
- The double-edged role and therapeutic potential of TREM2 in atherosclerosis.Biomarker research · 2024Review
- Biophysical mapping of TREM2-ligand interactions reveals shared surfaces for engagement of multiple Alzheimer's disease ligands.Research square · 2024Article
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
Triggering receptor expressed on myeloid cells 2 (TREM2) is a single-pass transmembrane receptor of the immunoglobulin superfamily that is secreted in a soluble (sTREM2) form. Mutations in TREM2 have been linked to increased risk of Alzheimer's disease (AD). A prominent neuropathological component of AD is deposition of the amyloid-β (Aβ) into plaques, particularly Aβ40 and Aβ42. While the membrane-bound form of TREM2 is known to facilitate uptake of Aβ fibrils and the polarization of microglial processes toward amyloid plaques, the role of its soluble ectodomain, particularly in interactions with monomeric or fibrillar Aβ, has been less clear. Our results demonstrate that sTREM2 does not bind to monomeric Aβ40 and Aβ42, even at a high micromolar concentration, while it does bind to fibrillar Aβ42 and Aβ40 with equal affinities (2.6 ± 0.3 µM and 2.3 ± 0.4 µM). Kinetic analysis shows that sTREM2 inhibits the secondary nucleation step in the fibrillization of Aβ, while having little effect on the primary nucleation pathway. Furthermore, binding of sTREM2 to fibrils markedly enhanced uptake of fibrils into human microglial and neuroglioma derived cell lines. The disease-associated sTREM2 mutant, R47H, displayed little to no effect on fibril nucleation and binding, but it decreased uptake and functional responses markedly. We also probed the structure of the WT sTREM2-Aβ fibril complex using integrative molecular modeling based primarily on the cross-linking mass spectrometry data. The model shows that sTREM2 binds fibrils along one face of the structure, leaving a second, mutation-sensitive site free to mediate cellular binding and uptake.
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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.