title: Aβ and tau toxicities in Alzheimer's are linked via oxidative stress-induced p38 activation: protective role of vitamin E.
abstract: Oxidative stress is a hallmark of Alzheimer's disease (AD). We propose that rather than causing damage because of the action of free radicals, oxidative stress deranges signaling pathways leading to tau hyperphosphorylation, a hallmark of the disease. Indeed, incubation of neurons in culture with 5 µM beta-amyloid peptide (Aβ) causes an activation of p38 MAPK (p38) that leads to tau hyperphosphorylation. Inhibition of p38 prevents Aβ-induced tau phosphorylation. Aβ-induced effects are prevented when neurons are co-incubated with trolox (the water-soluble analog of vitamin E). We have confirmed these results in vivo, in APP/PS1 double transgenic mice of AD. We have found that APP/PS1 transgenic mice exhibit a high level of P-p38 in the hippocampus but not in cortex and this is prevented by feeding animals with a diet supplemented with vitamin E. Our results underpin the role of oxidative stress in the altered cell signaling in AD pathology and suggest that antioxidant prevention may be useful in AD therapeutics.
authors: Department of Physiology, Faculty of Medicine, University of Valencia, Fundacion Investigacion Hospital Clinico Universitario/INCLIVA, Avda. Blasco Ibañez, 15, Valencia 46010, Spain.
authors: E
authors: E
authors: Giraldo
authors: Department of Physiology, Faculty of Medicine, University of Valencia, Fundacion Investigacion Hospital Clinico Universitario/INCLIVA, Avda. Blasco Ibañez, 15, Valencia 46010, Spain.
authors: A
authors: A
authors: Lloret
authors: Department of Physiology, Faculty of Medicine, University of Valencia, Fundacion Investigacion Hospital Clinico Universitario/INCLIVA, Avda. Blasco Ibañez, 15, Valencia 46010, Spain.
authors: T
authors: T
authors: Fuchsberger
authors: Department of Physiology, Faculty of Medicine, University of Valencia, Fundacion Investigacion Hospital Clinico Universitario/INCLIVA, Avda. Blasco Ibañez, 15, Valencia 46010, Spain.
authors: J
authors: J
authors: Viña
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D014810:Vitamin E / Q000031:analogs & derivatives / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D020011:Protective Agents; D016875:tau Proteins; D014810:Vitamin E; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Antioxidant; Beta-amyloid; P-p38; Vitamin E