Abstract
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, PrPC, specifically inhibits the polymerization of Aβ 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 Aβ receptors, FcγRIIb and LilrB2, affect Aβ fibril growth in a manner similar to PrPC. 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.
Highlights
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
Recombinant PrP was fluorescently labeled by substituting a cysteine residue at position 34, and reacting it with a maleimide derivative of either Alexa Fluor 555 (AF555) or Alexa Fluor 488 (AF488)
While many previous studies have characterized the binding reaction using biochemical or cellbased methods, we have employed super-resolution microscopy (SRM) to directly visualize Aβreceptor interactions at nanoscale resolution. This approach has allowed us to elucidate a unique structural mechanism by which one important receptor, PrPC, influences the Aβ assembly process, and how it interacts with both Aβ fibrils as well as neurotoxic Aβ protofibrils and oligomers
Summary
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. 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. Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is characterized by accumulation within the brain of extracellular plaques composed of the amyloid-β (Aβ) peptide, and intracellular neurofibrillary tangles containing abnormally phosphorylated forms of the tau protein[1,2] These two kinds of pathological deposits lead to synaptic loss and dysfunction, and to degeneration and loss of neurons. That study, which relied upon biochemical assays and mathematical modeling, demonstrated that PrPC inhibits the elongation step of Aβ polymerization, most likely by binding to the ends of growing fibrils. We did not directly prove this mechanism by measurement of fibril elongation rates, or by localization PrP on individual fibrils
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