title: Deposition of iron and beta-amyloid plaques is associated with cortical cellular damage in rabbits fed with long-term cholesterol-enriched diets.
abstract: Hypercholesterolemia is a potential trigger of Alzheimer's disease, and is thought to increase brain levels of beta-amyloid (Abeta) and iron. However, animal models to address the mechanisms by which Abeta 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 Abeta peptide in the brain. Iron preferentially accumulated around Abeta plaques in the adjacent cortex, but was not found in the hippocampus. Co-localization of iron and Abeta 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.
authors.affiliation: Department of Pharmacology, Physiology and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, 58202, USA. oghribi@medicine.nodak.edu
authors.forename: Othman
authors.initials: O
authors.lastname: Ghribi
authors.forename: Mikhail Y
authors.initials: MY
authors.lastname: Golovko
authors.forename: Brian
authors.initials: B
authors.lastname: Larsen
authors.forename: Matthew
authors.initials: M
authors.lastname: Schrag
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Murphy
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000503:physiopathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002784:Cholesterol / Q000009:adverse effects / Q000378:metabolism*; D004195:Disease Models, Animal; D005293:Ferritins / Q000378:metabolism; D005526:Food, Formulated / Q000009:adverse effects; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006937:Hypercholesterolemia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D007501:Iron / Q000378:metabolism*; D019189:Iron Metabolism Disorders / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D018832:Molecular Chaperones / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D011817:Rabbits; D051742:Transcription Factor CHOP / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D018832:Molecular Chaperones; D051742:Transcription Factor CHOP; D005293:Ferritins; D002784:Cholesterol; D007501:Iron; D051547:Heme Oxygenase-1