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MRNA-Seq of the CA1 hippocampal subregion and liver from 3 month and 20 month old animals treated orally with vehicle or SAHA and mRNA-Seq of CA1 of 10 month old WT or APP/PS1-21 transgenic animals treated orally with vehicle or SAHA

ABSTRACT: Aging and increased amyloid burden are major risk factors for cognitive diseases such as Alzheimer's Disease (AD). An effective therapy does not yet exist. Here we use mouse models for age-associated memory impairment and amyloid deposition to study transcriptome and cell type-specific epigenome plasticity at the systems level in the brain and in peripheral organs. We show that at the level of epigenetic gene-expression aging and amyloid pathology are associated with inflammation and impaired synaptic function in the hippocampal CA1 region. While inflammation is associated with increased gene-expression that is linked to a subset of transcription factors, de-regulation of plasticity genes is mediated via different mechanisms in the amyloid and the aging model. Amyloid pathology impairs histone-acetylation and decreases expression of plasticity genes while aging affects differential splicing that is linked to altered H4K12 acetylation at the intron-exon junction in neurons but not in non-neuronal cells. We furthermore show that oral administration of the clinically approved histone deacetylase inhibitor Vorinostat not only restores spatial memory, but also exhibits an anti-inflammatory action and reinstates epigenetic balance and transcriptional homeostasis at the level of gene expression and exon usage. This is the first systems-level investigation of transcriptome plasticity in the hippocampal CA1 region in aging and AD models and of the effects of an orally dosed histone deacetylase inhibitor. Our data has important implications for the development of minimally invasive and cost-effective therapeutic strategies against age-associated cognitive decline. In fact, our data strongly suggest to test Vorinostat in patients suffering from AD.

ORGANISM(S): Mus musculus

PROVIDER: GSE63943 | GEO | 2015/08/17

SECONDARY ACCESSION(S): PRJNA269577

REPOSITORIES: GEO

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Project description:Metabolic, mitochondrial and behavioral correlations with transcriptional profiles from the CA1 and DG hippocampal regions of young and aged rhesus macaque. Increasing evidence indicates that obesity correlates with impaired cognitive performance during normal aging and is a major risk factor for Alzheimer’s disease. However, little is known regarding how peripheral metabolic variables affect cellular pathways in brain regions important for memory. Brain inflammation, mitochondrial dysregulation, and altered transcriptional regulation have all been found to occur with aging, and recent microarray analyses in rodent models have linked these processes and others to age-related memory impairment. However, whether these brain changes are also associated with metabolic variables is not known. Aging monkeys exhibit several metabolic changes similar to those seen in humans. Here, we tested peripheral-brain relationships in six young (7.0 +/- 0.3 years) and six aged (23.5 +/- 0.7 years) female rhesus monkeys. Animal cognition was gauged with a variable delay task; blood constituents were assessed with a serum chemistry panel emphasizing markers of metabolic dysfunction; mitochondrial function was measured from the hippocampus of one hemisphere; and the CA1 and dentate gyrus regions of the other hippocampus were dissected out for gene expression microarray analysis. Aged animals showed reduced performance on the behavioral task, exhibited aspects of metabolic dysregulation including increased insulin, triglyceride, and chylomicron levels (consolidated into a peripheral metabolic index), and showed a significant age-related reduction in State III oxidation, a measure of mitochondrial function. Microarray analyses revealed hundreds of genes that correlated with the peripheral metabolic index. However, DAVID statistical pathway analyses showed that upregulated inflammatory genes in CA1 and downregulated transcriptional regulation genes in dentate gyrus and CA1 were particularly overrepresented among genes correlated with the peripheral index. Thus, the association of metabolic variables with specific neuropathological processes in different regions of the hippocampal formation may have implications for mechanisms through which peripheral metabolism alters the risk for Alzheimer’s disease. Keywords: Rhesus hippocampal aging

Dataset Information

MRNA-Seq of the CA1 hippocampal subregion and liver from 3 month and 20 month old animals treated orally with vehicle or SAHA and mRNA-Seq of CA1 of 10 month old WT or APP/PS1-21 transgenic animals treated orally with vehicle or SAHA

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