title: PrP and beta-amyloid fragments activate different neurotoxic mechanisms in cultured mouse cells.
abstract: Alzheimer's disease and prion diseases such as Creutzfeldt-Jakob disease are caused by as yet undefined metabolic disturbances of normal cellular proteins, the amyloid precursor protein and the prion protein (PrP). Synthetic fragments of both proteins, beta-amyloid 25-35 (betaA25-35) and PrP106-126, have been shown to be toxic to neurons in culture. Cell death in both cases occurs by apoptosis. Here we show that there are considerable differences in the mechanisms involved. Thus, PrP106-126 is not toxic to cortical cell cultures of PrP knockout mouse neurons whereas betaA25-35 is. The toxicity of both peptides involves Ca2+ uptake through voltage-sensitive Ca2+ channels but only PrP106-126 toxicity involves the activity of NMDA receptors. The toxicity of betaA25-35, but not PrP106-126, is attenuated by the action of forskolin. These results indicate that PrP106-126 and PA25-35 induce neuronal apoptosis through different mechanisms.
authors.affiliation: Institut für Neuropathologie, Universität Göttingen, Germany.
authors.forename: D R
authors.initials: DR
authors.lastname: Brown
authors.forename: J W
authors.initials: JW
authors.lastname: Herms
authors.forename: B
authors.initials: B
authors.lastname: Schmidt
authors.forename: H A
authors.initials: HA
authors.lastname: Kretzschmar
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects*; D009498:Neurotoxins / Q000633:toxicity*; D010446:Peptide Fragments / Q000633:toxicity*; D011328:Prions / Q000633:toxicity*
chemical_list: D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D010446:Peptide Fragments; D011328:Prions; D000242:Cyclic AMP; D002118:Calcium