Identification and characterization of the conformation and size of amyloid- (42) oligomers targeting the receptor LilrB2

Experimental observations revealed that the amyloid-beta 42 oligomer (A beta O) can directly bind to the LilrB2 D1D2(LDD) receptor with nanomolar-affinity, leading to changes in synaptic plasticity and cognitive deficits. However, the dependence of neurotoxicity on the morphology, size, and aggregation stage (SP1, SP2) of A beta O, as well as the specific molecular mechanism of A beta O-LDD interaction, remain uncertain. To address these uncertainties, we investigated the interaction between the LDD neuroreceptor and A beta O with different A beta 42 species (nontoxic species, toxic species, and protofibril) and sizes. Our results showed that the LDD selectively binds A beta O species rather than the A beta 42 monomer, accommodating various A beta 42 dimers and trimers as well as SP2 A beta O, in a specific pose in the pocket of the LDD receptor (region I). Additionally, protofibrils with exposed beta 1/beta 2 regions can also bind to region I of the LDD receptor, as observed experimentally (Cao, et al., Nat. Chem., 2018, 10, 1213; and Aim et al., Nat. Commun., 2021, 12, 3451). More extensively, we identified two additional regions of the LDD receptor, regions II and III, suitable for binding to larger A beta O species at the SP1 with different molecular weights and conformations, accounting for the stronger binding strength obtained experimentally. We suggest that the two regions are more competitive than region I in causing toxicity by A beta O binding. The detailed and systematic characterization for the complexes generated between the LDD receptor and various A beta O species, including the protofibril, offers deep insight into the dependence of neurotoxicity on the A beta O size and conformation at the molecular level, and provides novel and specific targets for drug design of Alzheimer's disease.