Issue 37, 2023

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

Abstract

Experimental observations revealed that the amyloid-β 42 oligomer (AβO) 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 AβO, as well as the specific molecular mechanism of AβO–LDD interaction, remain uncertain. To address these uncertainties, we investigated the interaction between the LDD neuroreceptor and AβO with different Aβ42 species (nontoxic species, toxic species, and protofibril) and sizes. Our results showed that the LDD selectively binds AβO species rather than the Aβ42 monomer, accommodating various Aβ42 dimers and trimers as well as SP2 AβO, in a specific pose in the pocket of the LDD receptor (region I). Additionally, protofibrils with exposed β1/β2 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 AβO 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 AβO binding. The detailed and systematic characterization for the complexes generated between the LDD receptor and various AβO species, including the protofibril, offers deep insight into the dependence of neurotoxicity on the AβO size and conformation at the molecular level, and provides novel and specific targets for drug design of Alzheimer's disease.

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

Supplementary files

Article information

Article type
Paper
Submitted
13 Jun 2023
Accepted
31 Aug 2023
First published
04 Sep 2023

Phys. Chem. Chem. Phys., 2023,25, 25229-25239

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

J. Mei, W. Xu, W. Gao, C. Wang, Y. Guan, S. Ahmad and H. Ai, Phys. Chem. Chem. Phys., 2023, 25, 25229 DOI: 10.1039/D3CP02746E

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