Vitamin E Research Today is a free monthly online journal that collates and summarizes the latest research about Vitamin E, including details on benefits, dosage, supplements, antioxidants.

Role of glutathione in intracellular amyloid-alpha precursor protein/carboxy-terminal fragment aggregation and associated cytotoxicity.

Woltjer RL, Nghiem W, Maezawa I, Milatovic D, Vaisar T, Montine KS, Montine TJ

Department of Pathology, University of Washington, Seattle, 98104, USA. rwoltjer@u.washington.edu

Abstract Alterations in glutathione (GSH) metabolism are associated with neurodegeneration in Alzheimer's disease (AD), and GSH depletion follows application of exogenous fibrillar amyloid beta (Abeta) peptides in experimental systems; these results are commonly cited as evidence of oxidative damage in AD. We used MC65 human neuroblastoma cells that conditionally express carboxy-terminal fragments of the Abeta precursor protein (Abeta/CTFs) to directly test the hypothesis that GSH is part of the cellular response to stressors associated with Abeta/CTF accumulation and not simply a marker of oxidative damage. Our data showed that Abeta/CTFs accumulated by post-translational processes and were associated with progressive increases in oxidative damage and cytotoxicity. Ethycrinic acid (EA) or diethyl maleate (DEM), reagents that deplete GSH through non-specific thiol adduction, gave rise to dose-dependent cytotoxicity that was independent of Abeta/CTF expression and minimally responsive to alpha-tocopherol (AT). In contrast, buthionine sulfoximine (BSO), a selective inhibitor of GSH synthase, not only augmented Abeta/CTF-associated cell death but unexpectedly potentiated Abeta/CTF accumulation; both outcomes were completely suppressed by AT. These data suggest that antioxidants may serve as 'Abeta targeting' therapies that suppress toxic protein aggregation rather than simply acting as downstream radical scavengers.

Published 28 April 2005 in J Neurochem, 93(4): 1047-56.
Full-text of this article is available online (may require subscription).

© 2004-2008 Vitamin E Research Today. All Rights Reserved.