Role of cellular prion protein interaction with Ab42

Soluble Abeta oligomers are widely recognised as the toxic forms responsible for triggering AD and Abeta receptors are hypothesized to represent the first step in a neuronal cascade leading to dementia. Cellular prion protein (PrP) has been reported as a high-affinity binder of Ab oligomers. The interactions of PrP with both Ab 42 and the highly toxic N-truncated pyroglutamylated species (AbpE3-42) are here investigated, at a molecular level, by means of ThT fluorescence, NMR and TEM. We demonstrate that soluble PrP binds both Ab42 and AbpE3-42, preferentially interacting with oligomeric species and delaying fibril formation. Residue level analysis of Ab42 oligomerization process reveals, for the first time, that PrP is able to differently interact with the forming oligomers, depending on the aggregation state of the starting Ab42 sample. A distinct behavior is observed for Ab42 N-terminal and C-terminal residues, suggesting that PrP protects Ab42 N-tail from entangling on the mature NMR invisible fibril, consistent with the hypothesis that Ab42 N-tail is the locus of interaction with PrP. PrP/AbpE3-42 interactions are here reported for the first time. All interaction data are validated and complemented by cellular tests performed on Wt and PrP-silenced neuronal cell lines, clearly showing PrP dependent Ab oligomer cell internalization and toxicity. The ability of soluble PrP to compete for Ab oligomers binding with membrane-anchored PrP bears relevance for studies of druggable pathways.