Aβ receptors specifically recognize molecular features displayed by fibril ends and neurotoxic oligomers

• Published in: Nature communications Vol. 12; no. 1; pp. 3451 - 16
• Main Authors: Amin, Ladan, Harris, David A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.06.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 14; 14/19; 14/28; 631/1647/328/2238; 631/378/1689/1283; 631/45/460; 82/51; 82/83; Alzheimer's disease; Amyloid - metabolism; Amyloid beta-Peptides - metabolism; Animals; Assemblies; Benzothiazoles - metabolism; Binding; Calmodulin - metabolism; Cell surface; Elongation; Feature recognition; Fibrils; Humanities and Social Sciences; Humans; Kinetics; Mice; Models, Biological; Molecular interactions; multidisciplinary; Neurodegenerative diseases; Neurotoxicity; Neurotoxins - chemistry; Oligomers; Polymerization; Prions - metabolism; Protein Binding; Protein Multimerization; Receptors; Receptors, Cell Surface - metabolism; Receptors, IgG - metabolism; Receptors, Immunologic - metabolism; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23507-z

Several cell-surface receptors for neurotoxic forms of amyloid-β (Aβ) have been described, but their molecular interactions with Aβ assemblies and their relative contributions to mediating Alzheimer’s disease pathology have remained uncertain. Here, we used super-resolution microscopy to directly visualize Aβ-receptor interactions at the nanometer scale. We report that one documented Aβ receptor, PrP C , specifically inhibits the polymerization of Aβ fibrils by binding to the rapidly growing end of each fibril, thereby blocking polarized elongation at that end. PrP C binds neurotoxic oligomers and protofibrils in a similar fashion, suggesting that it may recognize a common, end-specific, structural motif on all of these assemblies. Finally, two other Aβ receptors, FcγRIIb and LilrB2, affect Aβ fibril growth in a manner similar to PrP C . Our results suggest that receptors may trap Aβ oligomers and protofibrils on the neuronal surface by binding to a common molecular determinant on these assemblies, thereby initiating a neurotoxic signal. PrP C , a receptor for Aβ oligomers, blocks polarized elongation of Aβ fibrils by binding to the rapidly growing end of each fibril. PrP C and other receptors may trap Aβ oligomers and protofibrils on the neuronal surface by binding to a common molecular determinant, initiating a neurotoxic signal.