title: Expression of a truncated human tau protein induces aqueous-phase free radicals in a rat model of tauopathy: implications for targeted antioxidative therapy.
abstract: Oxidative stress has been implicated in the pathogenesis of many neurodegenerative diseases including Alzheimer's disease (AD). We investigated the effect of a truncated form of the human tau protein in the neurons of transgenic rats. Using electron paramagnetic resonance we observed significantly increased accumulation of ascorbyl free radicals in brains of transgenic animals (up to 1.5-fold increase; P < 0.01). Examination of an in vitro model of cultured rat corticohippocampal neurons revealed that even relatively low level expression of human truncated tau protein (equal to 50% of endogenous tau) induced oxidative stress that resulted in increased depolarization of mitochondria (approximately 1.2-fold above control, P < 0.01) and increases in reactive oxygen species (approximately 1.3-fold above control, P < 0.001). We show that mitochondrial damage-associated oxidative stress is an early event in neurodegeneration. Furthermore, using two common antioxidants (vitamin C and E), we were able significantly eliminate tau-induced elevation of reactive oxygen species. Interestingly, vitamin C was found to be selective in the scavenging activity, suggesting that expression of truncated tau protein preferentially leads to increases in aqueous phase oxidants and free radicals such as hydrogen peroxide and hydroxyl and superoxide radicals. Our results suggest that antioxidant strategies designed to treat AD should focus on elimination of aqueous phase oxidants and free radicals.
authors: Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia.
authors: Martin
authors: M
authors: Cente
authors: Peter
authors: P
authors: Filipcik
authors: Stanislava
authors: S
authors: Mandakova
authors: Norbert
authors: N
authors: Zilka
authors: Gabriela
authors: G
authors: Krajciova
authors: Michal
authors: M
authors: Novak
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D003683:Dehydroascorbic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D055647:Rats, Transgenic; D017382:Reactive Oxygen Species / Q000378:metabolism*; D024801:Tauopathies / Q000378:metabolism*; D014810:Vitamin E / Q000494:pharmacology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D005609:Free Radicals; D017382:Reactive Oxygen Species; D016875:tau Proteins; D014810:Vitamin E; C000820:semidehydroascorbic acid; D001205:Ascorbic Acid; D003683:Dehydroascorbic Acid