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The Guinea Pig as a Model for Sporadic Alzheimer's Disease (AD): The Impact of Cholesterol Intake on Expression of AD-Related Genes.

ABSTRACT: 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 A? peptide sequence identical to human A?. 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 (?-secretase) transcription and down-regulation of ADAM10 (?-secretase) transcription which should increase release of A? 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 ?-secretase activity and A? 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, A? 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.

SUBMITTER: Sharman MJ

PROVIDER: S-EPMC3689723 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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The Guinea Pig as a Model for Sporadic Alzheimer's Disease (AD): The Impact of Cholesterol Intake on Expression of AD-Related Genes.

Sharman Mathew J MJ Moussavi Nik Seyyed H SH Chen Mengqi M MM Ong Daniel D Wijaya Linda L Laws Simon M SM Taddei Kevin K Newman Morgan M Lardelli Michael M Martins Ralph N RN Verdile Giuseppe G

PloS one 20130621 6

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) trans ...[more]

PMID: 23805206

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Project description:Introduction: Though heavy alcohol drinking has been well characterized as causing a variety of injuries, recent epidemiological evidence in humans suggests moderate consumption may provide beneficial effects. For example, there exists a J- or U-shaped relationship between the level of alcohol intake and cardiovascular disease risk. We investigated the underlying mechanisms of these positive consequences by identifying which genes are responsive to moderate alcohol intake in the liver, the primary site for alcohol metabolism. Methods: Twelve female, inbred, alcohol-preferring (iP10a) rats were split equally between chronic water exposure and voluntary chronic ethanol exposure. Hepatic cholesterol and triglyceride levels were analyzed both histologically and biochemically. Hepatic transcriptomes were paired-end sequenced on the Illumina HiScanSQ system. Reads were analyzed and mapped using CLCbio Genomics Workbench 4.9. We confirmed altered expression of a subset of genes using TaqMan-based qRT-PCR. To quantify DNA methylation, we first digested DNA with methylation sensitive restriction enzymes and then performed qPCR using TaqMan assays surrounding the digest sites. Calculating M-NM-^TCt between a mock digest and digest determines the percent methylation in that locus. Results: Voluntary alcohol consumption in iP10a rats modeled moderate consumption in humans. These levels did not result in intrahepatic fat accumulation. Sequencing produced ~1.2 Gb of sequence per sample, and 65% of reads mapped uniquely. Using a FDR corrected p value of 0.05 we found 250 altered transcripts. Ontology analysis of genes with a fold change M-bM-^IM-%1.3 identified many cholesterol synthesis genes and cytoskeleton subunit genes, all of which were down-regulated. Of the 28 genes reanalyzed by qRT-PCR, altered expression was confirmed in 24 genes including the majority of the cholesterol synthesis and cytoskeleton subunit genes. Lastly, we profiled methylation throughout the promoter and gene body of four genes elicited in the RNA-Seq experiment. We found that alcohol caused demethylation at all loci; however this loss happened in a site-specific, tightly regulated manner. Conclusion: Voluntary consumption in the iP10a animals models moderate consumption in humans, does not produce intrahepatic fat accumulation, and causes down-regulation of a majority of cholesterol synthesis genes. Moderate alcohol also results in a tightly-regulated demethylation effect. Our results explain, at least in part, the J- or U-shaped relationship between level of alcohol intake and cardiovascular disease risk. We sequenced 12 female iP10a rat hepatic transcriptomes providing 6 biological replicates for water control and 6 for ethanol treatment.

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Dataset Information

The Guinea Pig as a Model for Sporadic Alzheimer's Disease (AD): The Impact of Cholesterol Intake on Expression of AD-Related Genes.

Publications

The Guinea Pig as a Model for Sporadic Alzheimer's Disease (AD): The Impact of Cholesterol Intake on Expression of AD-Related Genes.

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