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
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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