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

Several cell-surface receptors for neurotoxic forms of amyloid-beta (A beta) have been described, but their molecular interactions with A beta assemblies and their relative contributions to mediating Alzheimer's disease pathology have remained uncertain. Here, we used super-resolution microscopy to directly visualize A beta -receptor interactions at the nanometer scale. We report that one documented A beta receptor, PrPC, specifically inhibits the polymerization of A beta fibrils by binding to the rapidly growing end of each fibril, thereby blocking polarized elongation at that end. PrPC 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 A beta receptors, Fc gamma RIIb and LilrB2, affect A beta fibril growth in a manner similar to PrPC. Our results suggest that receptors may trap A beta oligomers and protofibrils on the neuronal surface by binding to a common molecular determinant on these assemblies, thereby initiating a neurotoxic signal. PrPC, a receptor for A beta oligomers, blocks polarized elongation of A beta fibrils by binding to the rapidly growing end of each fibril. PrPC and other receptors may trap A beta oligomers and protofibrils on the neuronal surface by binding to a common molecular determinant, initiating a neurotoxic signal.

Automated summary

This study used super-resolution microscopy to visualize interactions between Aβ and cell-surface receptors. It found that the receptor PrPC inhibits Aβ fibril polymerization by binding to the growing end of each fibril. Other receptors like FcγRIIb and LilrB2 also affect Aβ fibril growth similarly to PrPC, suggesting a common mechanism in trapping Aβ assemblies on neuronal surfaces to initiate neurotoxic signals.