An apolipoprotein E4 fragment can promote intracellular accumulation of amyloid peptide beta 42

Ioannis Dafnis, Efstratios Stratikos, Athina Tzinia, Effie C. Tsilibary, Vassilis I. Zannis, Angeliki Chroni

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Apolipoprotein E (apoE) plays a crucial role in lipid transport in circulation and the brain. The apoE4 isoform is a major risk factor for Alzheimer's disease (AD). ApoE4 is more susceptible to proteolysis than other apoE isoforms and apoE4 fragments have been found in brains of AD patients. These apoE4 fragments have been hypothesized to be involved in the pathogenesis of AD, although the mechanism is not clear. In this study we examined the effect of lipid-free apoE4 on amyloid precursor protein processing and 40-amino-acid Aβ variant and 42-amino-acid Aβ variant levels in human neuroblastoma SK-N-SH cells. We discovered that a specific apoE4 fragment, apoE4[δ(166-299)], can promote the cellular uptake of extracellular 40-amino-acid Aβ variant and 42-amino-acid Aβ variant either generated after amyloid precursor protein transfection or added exogenously. A longer length fragment, apoE4[δ(186-299)], or full-length apoE4 failed to elicit this effect. ApoE4[δ(166-299)] effected a 20% reduction of cellular sphingomyelin levels, as well as changes in cellular membrane micro-fluidity. Following uptake, approximately 50% of 42-amino-acid Aβ variant remained within the cell for at least 24 h, and led to increased formation of reactive oxygen species. Overall, our findings suggest a direct link between two early events in the pathogenesis of AD, apoE4 proteolysis and intraneuronal presence of amyloid beta peptide.

Original languageEnglish (US)
Pages (from-to)873-884
Number of pages12
JournalJournal of Neurochemistry
Volume115
Issue number4
DOIs
StatePublished - Nov 2010

Keywords

  • Alzheimer's disease
  • Amyloid peptide beta
  • Apolipoprotein E
  • Apolipoprotein E4 fragments
  • Intracellular accumulation
  • Reactive oxygen species

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