Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Conserved epigenomic signatures between mouse and human elucidate immune basis of Alzheimer's disease

ABSTRACT: Alzheimer’s disease (AD) is a severe1 age-related neurodegenerative disorder characterized by accumulation of beta-amyloid (Aβ) plaques and neurofibrillary tangles, synaptic and neuronal loss, and cognitive decline. Several genes have been implicated in AD, but chromatin state alterations during neurodegeneration remain uncharacterized. Here, we profile transcriptional and chromatin state dynamics across early and late pathology in the hippocampus of an inducible mouse model of AD-like neurodegeneration. We find a coordinated downregulation of synaptic plasticity genes and regulatory regions, and upregulation of immune response genes and regulatory regions, which are targeted by factors that belong to the ETS family of transcriptional regulators, including PU.1. Human regions orthologous to increasing-level enhancers show immune cell-specific enhancer signatures as well as immune cell expression quantitative trait loci (eQTL), while decreasing-level enhancer orthologs show fetal brain specific enhancer activity. Surprisingly, AD-associated genetic variants are specifically enriched in increasing-level enhancer orthologs implicating immune processes in AD predisposition. Indeed, increasing enhancers overlap known AD loci lacking protein-altering variants and implicate additional loci that do not reach genome-wide significance. Our results reveal new insights into the mechanisms of neurodegeneration and establish the mouse as a useful model for functional studies of AD regulatory regions. We profiled gene expression levels through RNA-Seq and histone mark levels through ChIP-Seq to compare control mice to the CK-p25 Alzheimer's disease model at 2 weeks and 6 weeks after induction of neurodegeneration.

ORGANISM(S): Mus musculus

SUBMITTER: Andreas Pfenning

PROVIDER: E-GEOD-65159 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease.

Gjoneska Elizabeta E Pfenning Andreas R AR Mathys Hansruedi H Quon Gerald G Kundaje Anshul A Tsai Li-Huei LH Kellis Manolis M

Nature 20150201 7539

Alzheimer's disease (AD) is a severe age-related neurodegenerative disorder characterized by accumulation of amyloid-β plaques and neurofibrillary tangles, synaptic and neuronal loss, and cognitive decline. Several genes have been implicated in AD, but chromatin state alterations during neurodegeneration remain uncharacterized. Here we profile transcriptional and chromatin state dynamics across early and late pathology in the hippocampus of an inducible mouse model of AD-like neurodegeneration. ...[more]

PMID: 25693568

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Project description:INTRODUCTION Alzheimer’s disease (AD) is an advanced neurodegenerative disorder characterized by progressive impairment in both memory loss and cognitive capacities, which resulting in severe dementia [1]. The pathogenesis of AD is complicated and poorly understood. According to the World Alzheimer Report 2018, it is estimated that AD affects at least 50 million persons throughout the world, and the number of people with AD will double nearly every 20 years [2]. Over the past decade, various theories have been developed for the neuropathological level of AD, but the most popular distinct pathological hallmarks is extracellular accumulation of amyloid beta (Aβ) plaques, as well as the neurofibrillary tangles (NFTs) composed of the hyperphosphorylated tau in the form of in the select brain regions [3]. The other factors including mitochondrial dysfunction, oxidative stress, brain inflammation and neurotransmitter disturbances pathology have been recognized as a contributing factor in the pathogenesis of AD [4]. To date, only symptomatic therapies are available for AD patients. Cholinesterase inhibitors (CIs) are approved for mild to moderate AD patients, and memantine is the only one N-methyl-D-aspartate receptor (NMDAR) antagonist has been approved for moderate to severe AD [5]. NMDAR is a glutamate ionotropic receptor, they display high Ca2+ permeability and voltage-dependent block by Mg2+[6]. In AD patients, NMDARs could be overactivated due to increasing glutamate release from presynaptic neurons. Overactived NMDARs lead first to Ca2+ overload in postsynaptic neurons, followed by desensitization and internalization, resulting in synaptic dysfunction and ultimately cell death [7, 8]. The numerous factors than can influence the levels of endogenous glutamate release in the pathogenesis of AD, deposition of Aβplaques, soluble Aβoligomers, NFTs, mitochondrial dysfunction and oxidative stress have been associated with the higher concentration of glutamate release[9, 10]. Memantine is an uncompetitive, moderate affinity NMDA receptor (NMDAR) antagonist which is used for a further therapeutic option of moderate to severe AD [5]. Its effects have been investigated in a large number of in vitro and in vivo studies, which indicated that memantine can against Aβ-induced glutamate-mediated toxicity, attenuate phosphorylation of tau and reduces level of total precursor protein (APP) in human neuroblastoma SK-N-SH cells [11], and lower Aβ1-42 secretion and plaques in primary cortical neuronal culture cells [9, 12]. Some studies showed that memantine also completely protected against Aβ-induced ROS injure in the primary hippocampal neurons [13]. Studies with transgenic animal models showed that memantine reduced the levels of soluble Aβ1-42, Aβ plaque deposition and lowered the loss of synaptic density in APP/PS1mice [4, 14, 15], and decreased the levels of total tau and hyperphosphorylated tau in 3×Tg-AD mice [3]. Furthermore, memantine altered genes expression in adult rat brain [16], and modulated protein profiles in Down syndrome mice brain [17]. However, no comprehensive study of proteomic characteristics description of 3×Tg-AD transgenic mice under the memantine treatment has been conducted to date as far as we searched. In order to better understand the multiple actions of memantine, we conducted detailed analysis of proteomics and bioinformatics to dissect the molecular mechanisms of memantine for the treatment of AD.

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.

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Conserved epigenomic signatures between mouse and human elucidate immune basis of Alzheimer's disease

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Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease.

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