Dataset Information

Age- and Nicotine-Associated Gene Expression Changes in the Hippocampus of APP/PS1 Mice

ABSTRACT: The etiology of Alzheimer's disease (AD) has been intensively studied. However, little is known about the molecular alterations in early-stage and late-stage AD. Hence, we performed RNA sequencing and assessed differentially expressed genes (DEGs) in the hippocampus of 18-month and 7-month-old APP/PS1 mice. Moreover, the DEGs induced by treatment with nicotine, the nicotinic acetylcholine receptor agonist that is known to improve cognition in AD, were also analyzed in old and young APP/PS1 mice. When comparing old APP/PS1 mice with their younger littermates, we found an upregulation in genes associated with calcium overload, immune response, cancer, and synaptic function; the transcripts of 14 calcium ion channel subtypes were significantly increased in aged mice. In contrast, the downregulated genes in aged mice were associated with ribosomal components, mitochondrial respiratory chain complex, and metabolism. Through comparison with DEGs in normal aging from previous reports, we found that changes in calcium channel genes remained one of the prominent features in aged APP/PS1 mice. Nicotine treatment also induced changes in gene expression. Indeed, nicotine augmented glycerolipid metabolism, but inhibited PI3K and MAPK signaling in young mice. In contrast, nicotine affected genes associated with cell senescence and death in old mice. Our study suggests a potential network connection between calcium overload and cellular signaling, in which additional nicotinic activation might not be beneficial in late-stage AD

ORGANISM(S): Mus musculus

PROVIDER: GSE86828 | GEO | 2019/09/10

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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.

Project description:Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. So far, there is no effective treatment for this condition. Tetramethylpyrazine (TMP) is an alkaloid extracted from traditional Chinese medicine chuanxiong, which is mainly used in the treatment of ischemic stroke some related diseases. In this study, we studied the potential effects of TMP on AD progression by using two AD mouse models. 8-month-old 3xTg-AD mice received TMP treatment (10mg/kg/d) for 1 month, and 4-month-old APP/PS1-AD mice received TMP treatment (10mg/kg/d) for 2 months. The behavioral tests by step-down passive avoidance test (SDA), new object recognition (NOR) and Morris water maze (MWM) showed that TMP significantly improved the learning and memory impairment of two AD transgenic mice. In addition, TMP reduced Aß levels and tau phosphorylation. Venny analysis showed that 116 differentially expressed proteins were commonly changed in 3xTg mice vs WT mice and TMP treated mice vs untreated mice. The same, 130 differentially expressed proteins were commonly changed in APP/PS1 mice vs WT mice and TMP treated mice vs untreated mice. The functions of the common proteins modified by TMP in the two models were mainly related to mitochondrial function, synaptic function, cytoskeleton, GTP binding, ATP binding. Mitochondrial omics analysis revealed 21 and 20 differentially expressed mitochondrial proteins modified by TMP in 3xTg-AD mice and APP/PS1 mice, respectively. These differential proteins were located in mitochondrial inner membrane, mitochondrial outer membrane, mitochondrial gap and mitochondrial matrix, and the function of some proteins is closely related to oxidative phosphorylation of (OXPHOS). Western-blot further validated that TMP changed the expression of OXPHOS complex proteins (sdhb, ndufa10, uqcrfs1, cox5b, atp5a) in the hippocampus of the two AD mice. Taken together, our study demonstrated that TMP improved the cognitive impairment and AD-like pathology, and modified hippocampal proteome in the two AD mice models. The improvement of the behavioral and pathology might be associated with modification of mitochondrial protein profile by TMP. Our study suggested that TMP had the potential for the treatment of AD.

Dataset Information

Age- and Nicotine-Associated Gene Expression Changes in the Hippocampus of APP/PS1 Mice

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets