The effect of oxidative stress on amyloid precursor protein processing in cells engaged in β-amyloidosis is related to apolipoprotein E genotype

Bozena Mazur-Kolecka, Dagmar Kowal, Thirasak Sukontasup, Dennis Dickson, Janusz Frackowiak

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

The reduced antioxidative defense in allele E4 carriers is suggested to contribute to β-amyloidosis in Alzheimer's disease and Down's syndrome. We studied the effect of oxidative stress on accumulation of amyloid-β peptide (Aβ) in vascular smooth muscle cells (SMCs) that are engaged in production of amyloid-β in vivo. Previously, we found that oxidative stress caused by ferrous ions induced accumulation of Aβ-apolipoprotein E deposits in lysosomes and was associated with a greater oxidative protein damage in E4 carriers. Here, we demonstrate that ferrous ions induce formation of Aβ deposits also in vascular tunica media in organotypic cultures of whole brain vessels, suggesting the role of oxidative stress in development of vascular β-amyloidosis. Cellular accumulation of Aβ in SMCs treated with ferrous ions was associated with a greater accumulation of C-terminal amyloid precursor protein (APP) fragments in E-4/E-4 than in E3/E3 myocytes and reduced the amount of soluble APPα in E3/E3, but not E-4/E-4, cultures. Antioxidant vitamin E prevented these effects, and, when applied alone, diminished the amount of APP C-terminal fragments and increased the amount of secreted APP in E3/E3, but not E-4/E-4, cells. C-terminal APP-immunoreacive material was accumulated in lysosomes partly with Aβ- and N-terminal APP immunoreactivities. These results suggest that the increased accumulation of APP and its fragments in lysosomes may yield additional amounts of cellular Aβ, particularly in E4 carriers. We hypothesize that the altered processing of APP in SMCs locally exposed to oxidative stress facilitates cellular deposition of Aβ and contribute to the increased risk of development of β-amyloidosis in E4/E4 carriers.

Original languageEnglish (US)
Pages (from-to)287-294
Number of pages8
JournalActa neuropathologica
Volume108
Issue number4
DOIs
StatePublished - Oct 1 2004

Keywords

  • Amyloid precursor protein turnover
  • Amyloid-β peptide accumulation
  • Apolipoprotein E genotype
  • Oxidative stress
  • Smooth muscle cells

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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