Effects of chemical chaperones on oxidative stress and detergent-insoluble species formation following conditional expression of amyloid precursor protein carboxy-terminal fragment

Randall L. Woltjer, Wendy McMahan, Dejan Milatovic, John D. Kjerulf, Feng Shiun Shie, Lisa G. Rung, Kathleen S. Montine, Thomas J. Montine

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Oxidative stress, protein misfolding, protein complex formation, and detergent insolubility are biochemical features of Alzheimer's disease (AD). We tested the cause-and-effect relationships among these using MC65 human neuroblastoma cells that exhibit toxicity upon conditional expression of carboxy-terminal fragments (CTFs) of the human amyloid precursor protein (APP). Treatments with three different antioxidants (α-tocopherol, N-acetyl cysteine, and α-lipoic acid) or three different compounds (glycerol, trimethylamine-N-oxide, and 4-phenylbutyric acid) that have been described to have a "chemical chaperone" function in promoting protein folding all had a protective effect on MC65 cells and decreased markers of oxidative damage and accumulation of high molecular weight amyloid (A) β-immunoreactive (IR) species. However, chaperones partially reduced detergent insolubility of the remaining Aβ-IR species, while antioxidants did not. These results suggest that protein misfolding associated with overexpression of APP CTFs promotes oxidative stress and cytotoxicity and contributes to formation of detergent-insoluble species that appear unrelated to cytotoxicity.

Original languageEnglish (US)
Pages (from-to)427-437
Number of pages11
JournalNeurobiology of Disease
Volume25
Issue number2
DOIs
StatePublished - Feb 1 2007

Keywords

  • Alzheimer's disease
  • Amyloid precursor protein
  • Antioxidants
  • Chaperones
  • Unfolded protein response

ASJC Scopus subject areas

  • Neurology

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