Expression of a Truncated Human Tau Protein Induces Aqueous-Phase Free Radicals in a Rat Model of Tauopathy: Implications for Targeted Antioxidative Therapy

Article type: Research Article

Authors: Cente, Martin^a | Filipcik, Peter^{a; b} | Mandakova, Stanislava^b | Zilka, Norbert^{a; b} | Krajciova, Gabriela^a | Novak, Michal^{a; b; *}

Affiliations: [a] Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia | [b] Axon Neuroscience GmbH, Vienna, Austria

Correspondence: [*] Corresponding author: Prof. Michal Novak, DrSc, Institute of Neuroimmunology, SAS, Dubravska cesta 9, 845 10 Bratislava, Slovakia. Tel.: +421 2 5478 8100; Fax: +421 2 5477 4276; E-mail: [email protected].

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 (∼1.2-fold above control, P < 0.01) and increases in reactive oxygen species (∼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.

Keywords: Antioxidants, oxidative stress, transgenic rat, truncated tau

DOI: 10.3233/JAD-2009-1107

Journal: Journal of Alzheimer's Disease, vol. 17, no. 4, pp. 913-920, 2009