Abstract
A fragment of the human prion protein, PrP106-126, has been used model the neurotoxicity of PrPscin vitro. The mechanism of action of PrP106-126 was demonstrated to require the presence of microglia and neuronal expression of PrPc. We show that PrP106-126 exists in a random coil state in water. The peptide acquires β–sheet structure on incubation in a salt solution. This β–sheet content increases greatly when the peptide is incubated for a month in water before analysis. Microglia are selectively activated by highly aggregated PrP106-126 with high β–sheet content and release high levels of superoxide. Less aggregated PrP106-126 with low β–sheet content is necessary for direct effects on neurones, reducing their resistance to oxidative stress by inhibiting the activity of superoxide dismutase. These results demonstrate that different components of the neurotoxic mechanism of PrP106-126 can be related to peptide subspecies differing in aggregation state and β–sheet content.
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