Abstract

Human cellular prion protein (PrPc) is involved in several neurodegenerative disorders; however, its normal function is unknown. We report here that a synthetic peptide corresponding to the four-octarepeat sequence of the PrPc (PrP59-91) protects hippocampal neurons against copper neurotoxic effects in vivo. Using a rat bilateral intrahippocampal injection model, we found that PrP59-91 protects against copper-induced neurotoxicity, including a recovery in spatial learning performance and a reduced neuronal cell loss and astrogliosis. Previous studies from our laboratory indicated that a tryptophan (Trp) residue plays a key role in the reduction of copper(II) to copper(I); therefore several PrP 59-91 fragments lacking histidine (His) and Trp residues were tested for their capacity to protect from copper toxicity. A PrP59-91 peptide lacking His residue shows as much neuroprotection as the native peptide; however, PrP59-91 without Trp residues only partially protected against copper toxicity. The neuroprotective effect not only occurs with PrP59-91, in fact a full neuroprotection was also observed using just one octamer of the N-terminal region of prion protein. We conclude that the N-terminal tandem octarepeat of the human PrPc protects neurons against copper toxicity by a differential contribution of the binding (His) and reducing (Trp) copper activities of PrP59-91. Our results are consistent with the idea that PrPc function is related to copper homeostasis.