Neurotoxic and Gliotrophic Activity of a Synthetic Peptide Homologous to Gerstmann–Sträussler–Scheinker Disease Amyloid Protein

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Abstract
Amyloid fibrils in Gerstmann–Sträussler–Scheinker (GSS) disease are composed of a fragment of the prion protein (PrP), the N and C termini of which correspond to ragged residues 81–90 and 144–153. A synthetic peptide spanning the sequence 82–146 (PrP 82–146) polymerizes into protease-resistant fibrils with the tinctorial properties of amyloid. We investigated the biological activity of PrP 82–146 and of two nonamyloidogenic variants of PrP 82–146 with scrambled amino acid sequence 106–126 or 127–146. Cortical neurons prepared from rat and mouse embryos were chronically exposed to the PrP 82–146 peptides (10–50 μm). PrP 82–146 and the partially scrambled peptides induced neuronal death with a similar dose–response pattern, indicating that neurotoxicity was independent of amyloid fibril formation. Neurotoxicity was significantly reduced by coadministration of an anti-oligomer antibody, suggesting that PrP 82–146 oligomers are primarily responsible for triggering cell death. Neurons from PrP knock-out (Prnp0/0) mice were significantly less sensitive to PrP 82–146 toxicity than neurons expressing PrP. The gliotrophic effect of PrP 82–146 was determined by [methyl-3H]-thymidine incorporation in cultured astrocytes. Treatment with PrP 82–146 stimulated [methyl-3H]-thymidine uptake 3.5-fold. This activity was significantly less when the 106–126 or 127–146 regions were disrupted, indicating that PrP 82–146 amyloid activates the gliotrophic response. Prnp0/0 astrocytes were insensitive to the proliferative stimulus of PrP 82–146. These results underline the role of cerebral accumulation of abnormally folded PrP fragments and indicate that cellular PrP governs the pathogenic process.