Soluble Prion Protein Inhibits Amyloid-β (Aβ) Fibrillization and Toxicity

The pathogenesis of Alzheimer disease appears to be strongly linked to the aggregation of amyloid-beta (A beta) peptide and, especially, formation of soluble A beta 1-42 oligomers. It was recently demonstrated that the cellular prion protein, PrPC, binds with high affinity to these oligomers, acting as a putative receptor that mediates at least some of their neurotoxic effects. Here we show that the soluble (i.e. glycophosphatidylinositol anchorfree) prion protein and its N-terminal fragment have a strong effect on the aggregation pathway of A beta 1-42, inhibiting its assembly into amyloid fibrils. Furthermore, the prion protein prevents formation of spherical oligomers that normally occur during A beta fibrillogenesis, acting as a potent inhibitor of A beta 1-42 toxicity as assessed in experiments with neuronal cell culture. These findings may provide a molecular level foundation to explain the reported protective action of the physiologically released N-terminal N1 fragment of PrPC against A beta neurotoxicity. They also suggest a novel approach to pharmacological intervention in Alzheimer disease.