Effects of Prion Protein on Abeta42 and Pyroglutamate-Modified Abetapy3-42 Oligomerization and Toxicity

SolubleAbeta oligomers are widely recognized as the toxic forms responsible for triggeringAD, 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 highaffinity binder of Abeta oligomers. The interactions of PrP with both Abeta42 and the highly toxic N-truncated pyroglutamylated species (AbetapE3-42) are here investigated, at a molecular level, by means of ThT fluorescence, NMR and TEM.We demonstrate that soluble PrP binds bothAbeta42 and AbetapE3-42, preferentially interacting with oligomeric species and delaying fibril formation. Residue level analysis of Abeta42 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 A?42 sample. A distinct behavior is observed for A?42 1- 30 region and C-terminal residues, suggesting that PrP protects Abeta42 N-tail from entangling on the matureNMR-invisible fibril, consistent with the hypothesis that Abeta42 N-tail is the locus of interaction with PrP. PrP/AbetapE3-42 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 Abeta oligomer cell internalization and toxicity. The ability of soluble PrP to compete with membrane-anchored PrP for binding to Abeta oligomers bears relevance for studies of druggable pathways.