Decreased thioredoxin and increased thioredoxin reductase levels in Alzheimer's disease brain

Mark A. Lovell, Chengsong Xie, S. Prasad Gabbita, William R. Markesbery

Research output: Contribution to journalArticlepeer-review

190 Scopus citations

Abstract

Increasing evidence supports the role of reactive oxygen species (ROS) in the pathogenesis of Alzheimer's disease (AD). Both in vivo and in vitro studies demonstrate that thioredoxin (Trx) and thioredoxin reductase (TR), the enzyme responsible for reduction of oxidized Trx, have protective roles against cytotoxicity mediated by the generation of ROS. The present study measured levels of Trx protein and activities of TR in the brain in AD compared with control subjects, and evaluated the possible protective role of TR and Trx against amyloid β-peptide (Aβ) toxicity in neuronal cultures. Analysis of Trx protein levels in 10 AD and 10 control subjects demonstrated a general decrease in all AD brain regions studied, with statistically significant decreases in the amygdala (p < .05), hippocampus/parahippocampal gyrus (p < .05), and marginally significant (p < .10) depletions in the superior and middle temporal gryi. Thioredoxin reductase activity levels were increased in all AD brain regions studied with statistically significant increases occurring in AD amygdala (p = .01) and cerebellum (p = .007). To investigate the protective effects of Trx and TR against Aβ-induced toxicity, primary hippocampal cultures were treated with Trx or TR in combination with toxic doses of Aβ. Treatment of cultures with Trx led to a statistically significant concentration-dependent enhancement in cell survival against Aβ-mediated toxicity as did treatment with TR. Together, these data suggest that, although TR is protective against Aβ-mediated toxicity, the increase observed in AD brain offers no protection due to the significant decrease in Trx levels. This decrease in the antioxidant Trx-TR system may contribute to the increased oxidative stress and subsequent neurodegeneration observed in the brain in AD. Copyright (C) 2000 Elsevier Science Inc.

Original languageEnglish
Pages (from-to)418-427
Number of pages10
JournalFree Radical Biology and Medicine
Volume28
Issue number3
DOIs
StatePublished - Feb 1 2000

Bibliographical note

Funding Information:
This work was supported by National Institues of Health grants 5P50-AG05144 and 1P01-AG05119, and grants from the Abercrombie Foundation and Kleberg Foundation. The authors thank Ms. Jane Meara for technical assistance and Ms. Paula Thomason for editorial assistance.

Keywords

  • Alzheimer's disease
  • Amyloid β-peptide
  • Free radicals
  • Oxidative stress
  • Thioredoxin
  • Thioredoxin reductase

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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