Deposition of iron and β-amyloid plaques is associated with cortical cellular damage in rabbits fed with long-term cholesterol-enriched diets

Othman Ghribi, Mikhail Y. Golovko, Brian Larsen, Matthew Schrag, Eric J. Murphy

Research output: Contribution to journalArticle

105 Scopus citations

Abstract

Hypercholesterolemia is a potential trigger of Alzheimer's disease, and is thought to increase brain levels of β-amyloid (Aβ) and iron. However, animal models to address the mechanisms by which Aβ and iron accumulation may cause neuronal damage are poorly defined. To address this question, we fed adult rabbits a 1% cholesterol-enriched diet for 7 months. This diet was associated with increased regional deposition of both iron and Aβ peptide in the brain. Iron preferentially accumulated around Aβ plaques in the adjacent cortex, but was not found in the hippocampus. Co-localization of iron and Aβ was accompanied by apoptosis, DNA damage, blood-brain barrier (BBB) disruption, as well as dysregulation in the level of the iron-regulatory proteins, ferritin and heme-oxygenase-1. We further demonstrate that the cholesterol diet-induced apoptosis is mediated by the activation of the endoplasmic reticulum stress pathway, involving the down-regulation of the endoplasmic reticulum chaperones, calreticulin, grp78 and grp94, and the activation of the growth and arrest DNA damage protein, gadd153. Our results suggest that BBB damage and disturbances in iron metabolism may render the cortex more vulnerable than the hippocampus to the cholesterol-induced cellular stress.

Original languageEnglish (US)
Pages (from-to)438-449
Number of pages12
JournalJournal of Neurochemistry
Volume99
Issue number2
DOIs
StatePublished - Oct 2006
Externally publishedYes

Keywords

  • Cholesterol
  • Endoplasmic reticulum
  • Heme-oxygenase-1
  • Iron
  • gadd153

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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