(267e) Synergistic Reduction in Interfacial Flexibility of TREM2R47H and ApoE4 May Underlie AD Pathology

BACKGROUND: The strongest genetic drivers of late-onset AD are ApoE4 and TREM2^R47H. Despite their critical roles, the mechanisms underlying their interactions remain poorly understood.

METHODS: We conducted microsecond-long molecular dynamics simulations of TREM2-ApoE complexes, including TREM2^R47H, validating our findings through comparison with published experimental data on TREM2-ApoE binding interactions.

RESULTS: Our simulations reveal TREM2^WT can sample an ‘open’ CDR2 conformation, challenging the prevailing notion that this conformation is pathogenic. TREM2^WT exhibits greater flexibility, accessing diverse CDR2 conformations, while rigidity in TREM2^R47H’s CDR2 may explain its reduced ligand-binding properties. ApoE2 facilitates dynamic reconfiguration of TREM2-ApoE2 complexes, which is absent with ApoE4. TREM2^R47H and ApoE4 mutually rigidify each other, suppressing interfacial flexibility.

DISCUSSION: Our findings suggest mechanisms underlying ApoE2’s neuroprotective functions, ApoE4’s pathogenicity, and the synergistic effects of ApoE4 and TREM2^R47H in AD. TREM2^WT’s flexibility and reconfiguration with ApoE2 may support microglial activation, while rigidity in TREM2^R47H-ApoE4 interactions may drive pathogenic signaling.