Structural Impact of Alzheimer's Disease Mutations on Transmembrane TREM2-DAP12 Interactions: An Atomistic Perspective

Triggering receptor expressed on myeloid cells 2 (TREM2) is an immunomodulatory receptor that plays a critical role in microglial activation through its association with the adaptor protein DNAX-activation protein 12 (DAP12). Genetic studies have identified rare TREM2 variants as key risk factors for Alzheimer's disease (AD), with mutations affecting both the extracellular and transmembrane domains. While the TREM2-DAP12 complex is essential for microglial activation and implicated in Alzheimer's disease pathology, the structural and mechanistic effects of transmembrane domain mutations, particularly within different TREM2 isoforms, remain unclear. In this study, we employ multi-scale molecular dynamics simulations to investigate the impact of six TREM2 mutations (four in isoform 1, two in isoform 2) and one wild-type control (isoform 2) on complex stability. By integrating coarse-grained and all-atom simulations with unsupervised machine learning techniques, we reveal distinct conformational states and residue-level interactions that govern complex formation. Our findings demonstrate how mutations such as W191X in TREM2 isoform 2 disrupt critical interactions, leading to destabilisation of the complex and potential impairments in neuroimmune signalling. These results provide new insights into the structural mechanisms linking TREM2 mutations to AD and offer a foundation for developing targeted therapeutic strategies.