ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2025
TREM2-apoE3 interactions and Alzheimer's disease: Molecular and structural insights and effects of TREM2 R47H and apoE4 variants.
Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 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
- APOEε4 attenuates early TREM2-mediated microglial responses and influences disease trajectories in dementia with Lewy bodies.Research square · 2026Article
- XL-MS and De Novo Protein Design Identified a Common Motif for TREM2 Binding.bioRxiv : the preprint server for biology · 2026Article
- Alzheimer's Disease: From Pathogenesis to Emerging Therapeutic Targets.Journal of clinical medicine · 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
- 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
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Authors and funding
6 authors.
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Abstract
introductionTriggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (apoE) are among the strongest Alzheimer's disease (AD) genetic risk factors. TREM2 and apoE3 direct interaction has been established; however, molecular and structural insight into TREM2-apoE3 interactions and effects of AD-associated variants on TREM2-apoE3 interactions are not fully understood.
methodsWe used consensus protein-protein docking and molecular dynamics simulations to determine an experimentally consistent TREM2-apoE3 complex structure and examine AD-associated TREM2 R47H, and apoE4 variants effects.
resultsOur experimentally consistent TREM2-apoE3 complex structure identified new potential TREM2-apoE3 interactions alongside the known interactions. TREM2-apoE3 interactions impacted TREM2 and apoE3 structures and conformations. AD-associated TREM2 R47H and apoE4 variants altered TREM2-apoE binding mode and conformational stability. DISCUSSION: This study determined an experimentally consistent TREM2-apoE3 complex structure and revealed a potential mechanism that AD-associated TREM2 R47H variant alters TREM2-apoE3 binding mode. Understanding TREM2-apoE interactions is important for developing therapeutics that regulate this interaction and prevent lost binding in AD-associated variants. HIGHLIGHTS: Triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) are two strong genetic risk factors for Alzheimer's disease (AD). An experimentally consistent TREM2-apoE3 complex structure was determined. New potential interaction interfaces between TREM2 and apoE3 were identified. TREM2-apoE3 interactions altered TREM2 and apoE3 conformation. AD-associated TREM2 R47H variant shifted apoE3 binding TREM2 into multimerization site. ApoE4 destabilized TREM2 and apoE conformations in TREM2-apoE complexes.
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