Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
Synergistic reduction in interfacial flexibility of TREM2R47H and ApoE4 may underlie AD pathology.
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Lietzke Emma E, Saeb David, Aldrich Emma C, Bruce Kimberley D, Sprenger Kayla G
Аннотация
BACKGROUND: The strongest genetic drivers of late-onset Alzheimer's disease (AD) are apolipoprotein E4 (ApoE4) and TREM2R47H. 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 TREM2R47H, validating our findings through comparison with published experimental data on TREM2-ApoE binding interactions.
RESULTS: Our simulations reveal TREM2WT can sample an "open" CDR2 conformation, challenging the prevailing notion that this conformation is pathogenic. TREM2WT exhibits greater flexibility, accessing diverse CDR2 conformations, while rigidity in TREM2R47H's CDR2 may explain its reduced ligand-binding properties. ApoE2 facilitates dynamic reconfiguration of TREM2-ApoE2 complexes, which is absent with ApoE4. TREM2R47H 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 TREM2R47H in AD. TREM2WT's flexibility and reconfiguration with ApoE2 may support microglial activation, while rigidity in TREM2R47H-ApoE4 interactions may drive pathogenic signaling.
HIGHLIGHTS: TREM2WT samples diverse CDR2 conformations, challenging prior assumptions that an "open" CDR2 state is solely pathogenic. ApoE2 promotes dynamic reconfiguration of TREM2-ApoE2 complexes, preserving TREM2WT's flexibility. ApoE4's hinge forms a unique binding pocket that enhances TREM2 binding. The TREM2R47H-ApoE4 complex exhibits mutual rigidity, suppressing CDR2 and hinge flexibility.
METHODS: We conducted microsecond-long molecular dynamics simulations of TREM2-ApoE complexes, including TREM2R47H, validating our findings through comparison with published experimental data on TREM2-ApoE binding interactions.
RESULTS: Our simulations reveal TREM2WT can sample an "open" CDR2 conformation, challenging the prevailing notion that this conformation is pathogenic. TREM2WT exhibits greater flexibility, accessing diverse CDR2 conformations, while rigidity in TREM2R47H's CDR2 may explain its reduced ligand-binding properties. ApoE2 facilitates dynamic reconfiguration of TREM2-ApoE2 complexes, which is absent with ApoE4. TREM2R47H 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 TREM2R47H in AD. TREM2WT's flexibility and reconfiguration with ApoE2 may support microglial activation, while rigidity in TREM2R47H-ApoE4 interactions may drive pathogenic signaling.
HIGHLIGHTS: TREM2WT samples diverse CDR2 conformations, challenging prior assumptions that an "open" CDR2 state is solely pathogenic. ApoE2 promotes dynamic reconfiguration of TREM2-ApoE2 complexes, preserving TREM2WT's flexibility. ApoE4's hinge forms a unique binding pocket that enhances TREM2 binding. The TREM2R47H-ApoE4 complex exhibits mutual rigidity, suppressing CDR2 and hinge flexibility.