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

Randall L. Woltjer, William Nghiem, Izumi Maezawa, Dejan Milatovic, Tomas Vaisar, Kathleen S. Montine, Thomas J. Montine

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)1047-1056
Number of pages10
JournalJournal of Neurochemistry
Volume93
Issue number4
DOIs
StatePublished - May 2005
Externally publishedYes

Keywords

  • α-tocopherol
  • Aggregation
  • Alzheimer's
  • Amyloid
  • Antioxidants
  • Glutathione

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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