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Deposition of iron and β‐amyloid plaques is associated with cortical cellular damage in rabbits fed with long‐term cholesterol‐enriched diets
Author(s) -
Ghribi Othman,
Golovko Mikhail Y.,
Larsen Brian,
Schrag Matthew,
Murphy Eric J.
Publication year - 2006
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.04079.x
Subject(s) - endoplasmic reticulum , hippocampus , calreticulin , ferritin , cholesterol , cortex (anatomy) , endocrinology , dna damage , amyloid beta , medicine , microbiology and biotechnology , biology , apoptosis , chemistry , biochemistry , peptide , neuroscience , dna
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.