Identification and Characterization of the Structure and Size of Aβ42 Oligomers Targeting the Receptor FcγRIIb.

Kam and colleagues discovered that FcγRIIb can specifically bind to Aβ42 oligomers (AβOs). The N-terminal residues F4 and D7 of Aβ42, as well as the W115 residue in domain D2 of FcγRIIb, are involved in this binding. However, the specificity of the FcγRIIb receptor's binding sites for AβOs and their dependence on different AβO species, including dimers (D/D), trimers (T/T), tetramers (Te/Te), and pentamers (P/P) during both the primary (P1) and secondary nucleation phases (P2), remains unknown. To address this, we employed molecular dynamics (MD) simulations to investigate the interactions between the extracellular domains D1 and D2 (FDD) of FcγRIIb and AβOs of varying sizes in the two different phases. We discovered that three specific fragments (f1, f2, and f3) of domain D2 in FDD are the primary binding sites for AβO species. Furthermore, among AβOs of the same molecular weight, those from the P2 phase exhibit a stronger binding affinity for FDD than those from the P1 phase. The distinction is ascribed to the stronger dependence on the hydrophobic residues in the β1 and β2 regions for the binding of AβOs in P2 (including T, Te, and P) than that (including D, Te, and P) in the P1 phase. In the P1 phase, these AβOs prefer to achieve binding to FDD through their N-terminal residues; however, by this, we identified that the species observed in Kam's experiment to bind FcγRIIb should probably be the tetrameric AβO (Te) in the P1 phase. Moreover, within both the P1 and P2 phases, we predicted that the trimeric AβO species in either the P1 or P2 phase is the strongest binding ligand for the FcγRIIb receptor. This study provides a comprehensive molecular perspective on the interaction between FcγRIIb and AβO in P2, which is of significant importance for the development of therapeutic strategies targeting Alzheimer's disease (AD) and autoimmune diseases.