To test for a role for the cellular prion protein (PrP c) in cell death, we used a PrP c-binding peptide. Retinal explants from neonatal rats or mice were kept in vitro for 24 h, and anisomycin (ANI) was used to induce apoptosis. The peptide activated both cAMP/protein kinase A (PKA) and Erk pathways, and partially prevented cell death induced by ANI in explants from wild-type rodents, but not from PrP c-null mice. Neuroprotection was abolished by treatment with phosphatidylinositol-specific phospholipase C, with human peptide 106–126, with certain antibodies to PrP c or with a PKA inhibitor, but not with a MEK/Erk inhibitor. In contrast, antibodies to PrP c that increased cAMP also induced neuroprotection. Thus, engagement of PrP c transduces neuroprotective signals through a cAMP/PKA-dependent pathway. PrP c may function as a trophic receptor, the activation of which leads to a neuroprotective state.