title: Molecular events linking cholesterol to Alzheimer's disease and inclusion body myositis in a rabbit model.
abstract: Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by cognitive impairment and dementia, resulting from progressive synaptic dysfunction, loss and neuronal cell death. Inclusion body myositis (IBM) is a skeletal muscle degenerative disease, displaying progressive proximal and distal muscle weakness, in association with muscle fiber atrophy, degeneration and death. Studies have shown that the late onset version of AD (LOAD) and sporadic IBM (sIBM) in muscle share many pathological features, including the presence of extracellular plaques of β-amyloid peptides and intracellular tangles of hyperphosphorylated tau proteins. High blood cholesterol is suggested to be a risk factor for LOAD. Many neuropathological changes of LOAD can be reproduced by feeding rabbits a 2% enriched cholesterol diet for 12 weeks. The cholesterol fed rabbit model also simultaneously develops sIBM like pathology, which makes it an ideal model to study the molecular mechanisms common to the development of both diseases. In the present study, we determined the changes of gene expression in rabbit brain and muscle during the progression of LOAD and sIBM pathology using a custom rabbit nucleotide microarray, followed by qRT-PCR analyses. Out of 869 unique transcripts screened, 47 genes showed differential expression between the control and the cholesterol-treated group during the 12 week period and 19 changed transcripts appeared to be common to LOAD and sIBM. The most notable changes are the upregulation of the hemoglobin gene family and the downregulation of the genes required for mitochondrial oxidative phosphorylation in both brain and muscle tissues throughout the time course. The significant overlap on the changes of gene expression in the brain and muscle of rabbits fed with cholesterol-enriched diet supports the notion that LOAD and sIBM may share a common etiology.
authors.affiliation: Human Health and Therapeutics, National Research Council of CanadaOttawa, Ontario, Canada, K1A 0R6; Faculties of Medicine, University of OttawaOttawa, Ontario, Canada, K1H 8M5.
authors.forename: Qing Yan
authors.initials: QY
authors.lastname: Liu
authors.affiliation: Human Health and Therapeutics, National Research Council of Canada Ottawa, Ontario, Canada, K1A 0R6.
authors.forename: Roger
authors.initials: R
authors.lastname: Koukiekolo
authors.affiliation: Human Health and Therapeutics, National Research Council of Canada Ottawa, Ontario, Canada, K1A 0R6.
authors.forename: Dong Ling
authors.initials: DL
authors.lastname: Zhang
authors.affiliation: Human Health and Therapeutics, National Research Council of Canada Ottawa, Ontario, Canada, K1A 0R6.
authors.forename: Brandon
authors.initials: B
authors.lastname: Smith
authors.affiliation: Human Health and Therapeutics, National Research Council of Canada Ottawa, Ontario, Canada, K1A 0R6.
authors.forename: Dao
authors.initials: D
authors.lastname: Ly
authors.affiliation: Human Health and Therapeutics, National Research Council of Canada Ottawa, Ontario, Canada, K1A 0R6.
authors.forename: Joy X
authors.initials: JX
authors.lastname: Lei
authors.affiliation: Department of Basic Sciences, School of Medicine and Health Sciences, University of North Dakota Grand Forks, ND 58202, USA.
authors.forename: Othman
authors.initials: O
authors.lastname: Ghribi
keywords: Alzheimer’s disease; gene expression; hemoglobin; mitochondrial oxidative phosphorylation; nucleotide microarray; rabbit AD model; sIBM