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.