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Characterization of the chromatin accessibility in an Alzheimer’s disease (AD) mouse model (RNA-Seq)

ABSTRACT: The assay for transposase-accessible chromatin by sequencing (ATAC-seq) was used to investigate the AD-associated chromatin reshaping in the APPswe/PS1dE9 (APP/PS1) mouse model. ATAC-seq data in the hippocampus of 8-month-old APP/PS1 mice were generated, and the relationship between chromatin accessibility and gene expression was analyzed in combination with RNA-sequencing.We identified 1690 increased AD-associated chromatin accessible regions in the hippocampal tissues of APP/PS1 mice and 1003 decreased chromatin accessible regions were considered to be related with declined AD-associated biological processes.In the APP/PS1 hippocampus, 1090 genes were found to be up-regulated and 1081 down-regulated. Interestingly, enhanced ATAC-seq signal was found in approximately 740 genes, with 43 exhibiting up-regulated mRNA levels.Our study reveals that alterations in chromatin accessibility may be an initial mechanism in AD pathogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE145907 | GEO | 2020/07/09

REPOSITORIES: GEO

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Project description:Alzheimer's disease (AD) is a severe neurodegenerative disorder. Clinical trials to identify agents to treat AD have failed, and its underlying molecular pathology and etiology remain elusive. Neuroinflammation is thought to play a key role in the progression of AD. Emerging evidence has identified lower Nicotinamide adenine dinucleotide (NAD+) levels as a major factor in neurodegeneration, especially in AD. NAD+ is an important metabolite in all human cells, as it is at the convergence of many central processes in cellular and mitochondrial maintenance, including DNA repair and mitophagy (the degradation of damaged mitochondria). Our previous work found that treatment of 3xTgAD mice with an NAD+ precursor, nicotinamide riboside (NR), can improve key AD features including tau phosphorylation and learning deficits in mice. Here we used the APP/PS1 AD mouse model to interrogate the effect of NR on neuroinflammation. Microarray analysis revealed major changes in pathways and genes associated with inflammation and the APP/PS1 mice had lower NAD+ levels than WT mice. Thus, seven months old mice were treated with NR for five months and their NAD+/NADH ratio increased. Brain neuroinflammation decreased as determined by decreased activation of astrocytes and microglia, decreased pro-inflammatory cytokines and chemokines in the brains of the APP/PS1 mice. NR decreased neuroinflammation by lowering the NLRP3 inflammasome and NF-κB pathways. NR also attenuated DNA damage and apoptosis in the AD mouse brains. NR dramatically decreased senescence in the hippocampus and cortex of AD mice, relative to controls. Recent studies suggest that cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) activation are associated with DNA damage and senescence. cGAS-STING was activated in AD mice and decreases after NR treatment. Suggesting that NR can diminish neuroinflammation and senescence through the cGAS-STING pathway. NR treatment also greatly improved cognition and synaptic function in the APP/PS1 mice. We propose that the cGAS-STING pathway should be evaluated as a potential novel therapeutic target in AD.

Project description:Neuroinflammation is a major contributor to disease progression in Alzheimer´s disease (AD) and is characterized by the activity of brain resident glial cells, in particular microglia cells. However, there is increasing evidence that peripheral immune cells infiltrate the brain at certain stages of AD progression and shape disease pathology. We recently identified CD8+ T-cells in the brain parenchyma of APP-PS1 transgenic mice being tightly associated with microglia as well as with neuronal structures. The functional role of CD8+ T-cells in the AD brain is however completely unexplored. Here, we demonstrate increased numbers of intra-parenchymal CD8+ T-cells in human AD post-mortem hippocampus, which was replicated in APP-PS1 mice. Also, aged WT mice show a remarkable infiltration of CD8+ T-cells, which was more pronounced and had an earlier onset in APP-PS1 mice. To address their functional relevance in AD, we successfully ablated the pool of CD8+ T-cells in the blood, spleen and brain from 12 months-old APP-PS1 and WT mice for a total of 4 weeks using an anti-CD8 antibody treatment. While the treatment at this time of disease stage did neither affect the cognitive outcome nor plaque pathology, RNAseq analysis of the hippocampal transcriptome from APP-PS1 mice lacking CD8+ T-cells revealed highly altered neuronal- and synapse-related gene expression including an up-regulation for neuronal immediate early genes (IEGs) such as the Activity Regulated Cytoskeleton Associated Protein (Arc) and the Neuronal PAS Domain Protein 4 (Npas4). Gene ontology enrichment analysis illustrated that the biological processes “regulation of neuronal synaptic plasticity” and the cellular components “postsynapses” were over-represented upon CD8+ T-cell ablation. Additionally, Kegg pathway analysis showed up-regulated pathways for “calcium signaling”, “long-term potentiation”, “glutamatergic synapse” and “axon guidance”. Therefore, we conclude that CD8+ T-cells infiltrate the aged and AD brain and that brain CD8+ T-cells might directly contribute to neuronal dysfunction in modulating synaptic plasticity. Further analysis will be essential to uncover the exact mechanism of how CD8+ T-cells modulate the neuronal landscape and thereby contribute to AD pathology.

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Characterization of the chromatin accessibility in an Alzheimer’s disease (AD) mouse model (RNA-Seq)

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