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

Abstract

ABSTRACTOligomeric forms of amyloid-β (Aβ) peptide are known to be the primary neurotoxic species in Alzheimer’s disease (AD), but how they interact with neurons to produce their deleterious effects is unclear. Over ten different cell-surface receptors for Aβ have been described, but their molecular interactions with Aβ assemblies and their relative contributions to mediating AD pathology have remained uncertain. In the present work, we have used super-resolution microscopy to directly visualize Aβ-receptor interactions at the nanometer scale. We report that one documented Aβ receptor, the cellular prion protein, PrPC, specifically inhibits the polymerization Aβ fibrils via a unique mechanism in which it binds specifically 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 candidate Aβ receptors, FcγRIIb and LilrB2, affect Aβ fibril growth in a manner similar to PrPC. Taken together, our results suggest that neurotoxic signaling by several different receptors may be activated by common molecular interactions with both fibrillar and oligomeric Aβ ligands. Targeting such interactions with small molecules represents an attractive therapeutic strategy for treatment of AD.