title: Overexpression of cellular prion protein (PrP(C)) prevents cognitive dysfunction and apoptotic neuronal cell death induced by amyloid-β (Aβ₁₋₄₀) administration in mice.
abstract: The cellular prion protein (PrP(C)) is a neuronal-anchored glycoprotein that has been associated with several functions in the CNS such as synaptic plasticity, learning and memory and neuroprotection. There is great interest in understanding the role of PrP(C) in the deleterious effects induced by the central accumulation of amyloid-β (Aβ) peptides, a pathological hallmark of Alzheimer's disease, but the existent results are still controversial. Here we compared the effects of a single intracerebroventricular (i.c.v.) injection of aggregated Aβ(1-40) peptide (400pmol/mouse) on the spatial learning and memory performance as well as hippocampal cell death biomarkers in adult wild type (Prnp(+/+)), PrP(C) knockout (Prnp(0/0)) and the PrP(C) overexpressing Tg-20 mice. Tg-20 mice, which present a fivefold increase in PrP(C) expression in comparison to wild type mice, were resistant to the Aβ(1-40)-induced spatial learning and memory impairments as indicated by reduced escape latencies to find the platform and higher percentage of time spent in the correct quadrant during training and probe test sessions of the water maze task. The protection against Aβ(1-40)-induced cognitive impairments observed in Tg-20 mice was accompanied by a significant decrease in the hippocampal expression of the activated caspase-3 protein and Bax/Bcl-2 ratio as well as reduced hippocampal cell damage assessed by MTT and propidium iodide incorporation assays. These findings indicate that the overexpression of PrP(C) prevents Aβ(1-40)-induced spatial learning and memory deficits in mice and that this response is mediated, at least in part, by the modulation of programed cell death pathways.
authors.affiliation: Departamento de Farmacologia, Universidade Federal de Santa Catarina, UFSC, Florianópolis, SC, Brazil.
authors.forename: D
authors.initials: D
authors.lastname: Rial
authors.forename: T C
authors.initials: TC
authors.lastname: Piermartiri
authors.forename: F S
authors.initials: FS
authors.lastname: Duarte
authors.forename: C I
authors.initials: CI
authors.lastname: Tasca
authors.forename: R
authors.initials: R
authors.lastname: Walz
authors.forename: R D
authors.initials: RD
authors.lastname: Prediger
mesh_terms: D016229:Amyloid beta-Peptides / Q000008:administration & dosage*; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced* / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000473:pathology; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects*; D010446:Peptide Fragments / Q000008:administration & dosage*; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D011419:Propidium; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects; D013778:Tetrazolium Salts; D013844:Thiazoles; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D013778:Tetrazolium Salts; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); D051028:bcl-2-Associated X Protein; D011419:Propidium; D053148:Caspase 3; C022616:thiazolyl blue