The Guinea Pig as a Model for Sporadic Alzheimer’s Disease (AD): The Impact of Cholesterol Intake on Expression of AD-Related Genes
Autor: | Giuseppe Verdile, Daniel Ong, Simon M. Laws, Mathew J. Sharman, Kevin Taddei, Linda K. Wijaya, Michael Lardelli, Mengqi M. Chen, Morgan Newman, Ralph N. Martins, Seyyed Hani Moussavi Nik |
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Rok vydání: | 2013 |
Předmět: |
Anatomy and Physiology
Epidemiology ADAM10 lcsh:Medicine Gene Expression Amyloid beta-Protein Precursor Mice 0302 clinical medicine Molecular Cell Biology Nutritional Physiological Phenomena lcsh:Science 2. Zero hunger Genetics Regulation of gene expression 0303 health sciences Multidisciplinary Brain Animal Models Cholesterol Neurology Medicine Alzheimer's disease Research Article Gene isoform medicine.medical_specialty Clinical Research Design Guinea Pigs Cavia Biology Neurological System Presenilin High cholesterol Guinea pig 03 medical and health sciences Model Organisms Alzheimer Disease Internal medicine Presenilin-2 Presenilin-1 medicine Animals Humans Amino Acid Sequence Animal Models of Disease Nutrition 030304 developmental biology Amyloid beta-Peptides lcsh:R biology.organism_classification medicine.disease Diet Rats Disease Models Animal Endocrinology Gene Expression Regulation lcsh:Q Dementia Amyloid Precursor Protein Secretases Sequence Alignment 030217 neurology & neurosurgery Neuroscience |
Zdroj: | PLoS ONE PLoS ONE, Vol 8, Iss 6, p e66235 (2013) |
ISSN: | 1932-6203 |
Popis: | We investigated the guinea pig, Cavia porcellus, as a model for Alzheimer's disease (AD), both in terms of the conservation of genes involved in AD and the regulatory responses of these to a known AD risk factor - high cholesterol intake. Unlike rats and mice, guinea pigs possess an Aβ peptide sequence identical to human Aβ. Consistent with the commonality between cardiovascular and AD risk factors in humans, we saw that a high cholesterol diet leads to up-regulation of BACE1 (β-secretase) transcription and down-regulation of ADAM10 (α-secretase) transcription which should increase release of Aβ from APP. Significantly, guinea pigs possess isoforms of AD-related genes found in humans but not present in mice or rats. For example, we discovered that the truncated PS2V isoform of human PSEN2, that is found at raised levels in AD brains and that increases γ-secretase activity and Aβ synthesis, is not uniquely human or aberrant as previously believed. We show that PS2V formation is up-regulated by hypoxia and a high-cholesterol diet while, consistent with observations in humans, Aβ concentrations are raised in some brain regions but not others. Also like humans, but unlike mice, the guinea pig gene encoding tau, MAPT, encodes isoforms with both three and four microtubule binding domains, and cholesterol alters the ratio of these isoforms. We conclude that AD-related genes are highly conserved and more similar to human than the rat or mouse. Guinea pigs represent a superior rodent model for analysis of the impact of dietary factors such as cholesterol on the regulation of AD-related genes. |
Databáze: | OpenAIRE |
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