ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2024
Multimerization of TREM2 is impaired by Alzheimer's disease-associated variants.
Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- 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
- Viral Mimicry of Alzheimer's Disease: Innate Sensing of Self-Nucleic Acids as a Driver of Glial Senescence.Journal of molecular neuroscience : MN · 2026Review
- Alzheimer's Disease: From Pathogenesis to Emerging Therapeutic Targets.Journal of clinical medicine · 2026Review
- Cholecalciferol (vitamin D3) is an agonist of the Alzheimer's disease-associated immune receptor TREM2.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- Parkinson's disease: spatiotemporal regulation and therapeutic prospects of TREM2-mediated microglial responses.NPJ Parkinson's disease · 2026Review
- Nutritional substrates and microglial metabolic fitness in brain aging and Alzheimer's disease: from lipid handling to TREM2-linked translation.Frontiers in nutrition · 2026Review
- TREM2 as a central hub of neuroimmune-metabolic crosstalk in central nervous system disorders: from microglial biology to therapeutic targeting.Frontiers in immunology · 2026Review
- Disturbed flow induces reprogramming of endothelial cells to immune-like and foam cells under hypercholesterolaemia during atherogenesis.Cardiovascular research · 2025Article
- Roles of TREM2 in Alzheimer's disease.Translational neurodegeneration · 2025Review
- TREM2-apoE3 interactions and Alzheimer's disease: Molecular and structural insights and effects of TREM2 R47H and apoE4 variants.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Biophysical mapping of TREM2-ligand interactions reveals shared surfaces for engagement of multiple Alzheimer's disease ligands.Molecular neurodegeneration · 2025Article
- Multimerization of TREM2 is impaired by Alzheimer's disease-associated variants.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
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7 authors.
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Abstract
introductionThe immune receptor triggering receptor expressed on myeloid cells 2 (TREM2) is among the strongest genetic risk factors for Alzheimer's disease (AD) and is a therapeutic target. TREM2 multimers have been identified in crystallography and implicated in the efficacy of antibody therapeutics; however, the molecular basis for TREM2 multimerization remains poorly understood.
methodsWe used molecular dynamics simulations and binding energy analysis to determine the effects of AD-associated variants on TREM2 multimerization and validated with experimental results.
resultsTREM2 trimers remained stably bound, driven primarily by salt bridge between residues D87 and R76 at the interface of TREM2 units. This salt bridge was disrupted by the AD-associated variants R47H and R98W and nearly ablated by the D87N variant. This decreased binding among TREM2 multimers was validated with co-immunoprecipitation assays. DISCUSSION: This study uncovers a molecular basis for TREM2 forming stable trimers and unveils a novel mechanism by which TREM2 variants may increase AD risk by disrupting TREM2 oligomerization to impair TREM2 normal function. HIGHLIGHTS: Triggering receptor expressed on myeloid cells 2 (TREM2) multimerization could regulate TREM2 activation and function. D87-R76 salt bridges at the interface of TREM2 units drive the formation of stable TREM2 dimers and trimers. Alzheimer's disease (AD)-associated R47H and R98W variants disrupt the D87-R76 salt bridge. The AD-associated D87N variant leads to complete loss of the D87-R76 salt bridge.
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