TREM2-apoE3 interactions and Alzheimer's disease: Molecular and structural insights and effects of TREM2 R47H and apoE4 variants

Abstract

Introduction: Triggering 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.

Methods: We 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.

Results: Our 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.

Keywords: AD‐associated TREM2 R47H variant; TREM2‐apoE3 complex structure; alzheimer's disease; apolipoprotein E4; binding free energy analyses; experimentally guided consensus protein–protein docking; molecular dynamics simulations; triggering receptor expressed on myeloid cells 2.