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Glutathione Articles - Alzheimer's

Role of Glutathione in Intracellular Amyloid-A Precursor Protein/Carboxy-Terminal Fragment Aggregation and Associated Cytotoxicity
Randall L. Woltjer, William Nghiem, Izumi Maezawa, Dejan Milatovic, Tomas Vaisar, Kathleen S. Montine and Thomas J. Montine
Journal of Neurochemistry. 2005; 93:1047–1056.
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ABSTRACT

Alterations in glutathione (GSH) metabolism are associated with neurodegeneration in Alzheimer’s disease (AD), and GSH depletion follows application of exogenous fibrillar amyloid b (Ab) 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 Ab precursor protein (Ab/CTFs) to directly test the hypothesis that GSH is part of the cellular response to stressors associated with Ab/CTF accumulation and not simply a marker of oxidative damage. Our data showed that Ab/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 dosedependent cytotoxicity that was independent of Ab/CTF expression and minimally responsive to a-tocopherol (AT). In contrast, buthionine sulfoximine (BSO), a selective inhibitor of GSH synthase, not only augmented Ab/CTF-associated cell death but unexpectedly potentiated Ab/CTF accumulation; both outcomes were completely suppressed by AT. These data suggest that antioxidants may serve as ‘Ab targeting’ therapies that suppress toxic protein aggregation rather than simply acting as downstream radical scavengers.

Keywords: aggregation, a-tocopherol, Alzheimer’s, amyloid, antioxidants, glutathione.

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