Cerebral tissue of the animal model data LC-MS/MS
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive
ORGANISM(S): Rattus Norvegicus (rat)
TISSUE(S): Brain
SUBMITTER: 
Bo Ma
LAB HEAD: Jianxun Liu
PROVIDER: PXD025480 | Pride | 2021-05-18
REPOSITORIES: Pride
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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.
2019-11-12 | PXD012110 | Pride
Project description:Cerebral organoids â three-dimensional cultures of human cerebral tissue derived from pluripotent stem cells â have emerged as models of human cortical development. However, the extent to which in vitro organoid systems recapitulate neural progenitor cell proliferation and neuronal differentiation programs observed in vivo remains unclear. Here we use single-cell RNA sequencing (scRNA-seq) to dissect and compare cell composition and progenitor-to-neuron lineage relationships in human cerebral organoids and fetal neocortex. Covariation network analysis using the fetal neocortex data reveals known and novel interactions among genes central to neural progenitor proliferation and neuronal differentiation. In the organoid, we detect diverse progenitors and differentiated cell types of neuronal and mesenchymal lineages, and identify cells that derived from regions resembling the fetal neocortex. We find that these organoid cortical cells use gene expression programs remarkably similar to those of the fetal tissue in order to organize into cerebral cortex-like regions. Our comparison of in vivo and in vitro cortical single cell transcriptomes illuminates the genetic features underlying human cortical development that can be studied in organoid cultures. 734 single-cell transcriptomes from human fetal neocortex or human cerebral organoids from multiple time points were analyzed in this study. All single cell samples were processed on the microfluidic Fluidigm C1 platform and contain 92 external RNA spike-ins. Fetal neocortex data were generated at 12 weeks post conception (chip 1: 81 cells; chip 2: 83 cells) and 13 weeks post conception (62 cells). Cerebral organoid data were generated from dissociated whole organoids derived from induced pluripotent stem cell line 409B2 (iPSC 409B2) at 33 days (40 cells), 35 days (68 cells), 37 days (71 cells), 41 days (74 cells), and 65 days (80 cells) after the start of embryoid body culture. Cerebral organoid data were also generated from microdissected cortical-like regions from H9 embryonic stem cell derived organoids at 53 days (region 1, 48 cells; region 2, 48 cells) or from iPSC 409B2 organoids at 58 days (region 3, 43 cells; region 4, 36 cells).
2015-12-07 | E-GEOD-75140 | biostudies-arrayexpress
Project description:Multiple sclerosis (MS) is a chronic, inflammatory, and demyelinating disease of the central nervous system (CNS). Ursolic acid (UA) can be used in the MS treatment with anti-inflammatory and neuroprotective activities. However, UA is insoluble in water, which may affect its medication effectiveness. In this study, we evaluated the pharmacological effects of UAOS-Na, a water-soluble UA derivative, on experimental autoimmune encephalomyelitis (EAE) mouse, explored its underlying mechanism, and verified the mechanism by in vitro and in vivo experiments. As we expected, UAOS-Na (30 mg/kg/d) delayed the onset time of EAE from 11.78 days post immunization (dpi) to 14.33 dpi, reduced the incidence from 90.0% to 42.9%, and was more effective than UA. UAOS-Na (60 mg/kg/d) significantly decreased the serum levels of IFN-γ, IL-17A, TNF-α and IL-6, reduced the mononuclear cell infiltration of spinal cord, and inhibited the overexpression of key transcription factors T-bet and ROR-γt of EAE mouse spinal cord and spleen. In addition, UAOS-Na attenuated demyelination and astrogliosis in the CNS of EAE and Cuprizone-induced mice. Mechanically, proteomics showed that 217 differential expression proteins (DEPs) were enriched and 215 were upregulated in EAE mice. After UAOS-Na treatment, 52 DEPs were enriched and 49 were downregulated, and these DEPs were markedly enriched in inositol phosphate metabolism, calcium, sphingolipid, cAMP, and antigen processing and presentation (APP) signaling pathways. Among them, there were few studies on APP signaling pathway related with MS. Therefore, we further investigated the effect of UAOS-Na on APP signaling pathway and found that UAOS-Na downregulated the protein levels of Tapbp and H2-T23 in MHC-I antigen presentation pathway and decreased the proliferation of splenic CD8 T cells, thereby inhibiting the CNS infiltration of CD8 T cells. Together, our findings demonstrated that UAOS-Na have both direct anti-demyelination and anti-inflammation effects. And it could reduce the inflammation of MS by downregulating the expression of Tapbp and H2-T23 in the MHC-I antigen presentation pathway.
2023-11-30 | PXD045108 | Pride
Project description:In our study, differential male nucleus events and development behaviors were revealed from the fertilized eggs in response to the sperm from males of genotypic sex determination (GSD) and temperature-dependent sex determination (TSD) in gibel carp. When the eggs of maternal fish were fertilized by the sperm from males of GSD, the fertilized egg encountered similar sexual reproduction events and behaviors. However, when the eggs of maternal fish were fertilized by the sperm from males of TSD, a typical process of gynogenesis was observed. To reveal the underlying molecular mechanism of differential sperm nucleus development behaviors in the fertilized eggs, iTRAQ-based quantitative semen proteomics were performed on three semen samples from three males of GSD and three semen samples from three males of TSD respectively.
2018-06-14 | PXD008919 | Pride
Project description:The pathophysiology of Alzheimer’s disease (AD) is multifactorial with characteristic extracellular accumulation of amyloid-beta (Aβ) and intraneuronal aggregation of hyperphosphorylated tau in the brain. Development of disease-modifying treatment for AD has been challenging. Recent studies suggest that deleterious alterations in neurovascular cells happens in parallel with Aβ accumulation, inducing tau pathology and necroptosis. Therefore, therapies targeting cellular Aβ and tau pathologies may provide a more effective strategy of disease intervention. Tetramethylpyrazine nitrone (TBN) is a nitrone derivative of tetramethylpyrazine, an active ingredient from Ligusticum wallichii Franchat (Chuanxiong). We previously showed that TBN is a potent scavenger of free radicals with multi-targeted neuroprotective effects in rat and monkey models of ischemic stroke. The present study aimed to investigate the anti-AD properties of TBN. We employed AD-related cellular model (N2a/APPswe) and transgenic mouse model (3×Tg-AD mouse) for mechanistic and behavioral studies. Our results showed that TBN markedly improved cognitive functions and reduced Aβ and hyperphosphorylated tau levels in mouse model. Further investigation of the underlying mechanisms revealed that TBN promoted non amyloidogenic processing pathway of amyloid precursor protein (APP) in N2a/APPswe in vitro. Moreover, TBN preserved synapses from dendritic spine loss and upregulated synaptic protein expressions in 3×Tg-AD mice. Proteomic analysis of 3×Tg-AD mouse hippocampal and cortical tissues showed that TBN induced neuroprotective effects through modulating mitophagy, MAPK and mTOR pathways. In particular, TBN significantly upregulated PINK1, a key protein for mitochondrial homeostasis, implicating PINK1 as a potential therapeutic target for AD. In summary, TBN improved cognitive functions in AD-related mouse model, inhibited Aβ production and tau hyperphosphorylation, and rescued synaptic loss and neuronal damage. Multiple mechanisms underlie the anti-AD effects of TBN including the modulation of APP processing, mTOR signaling and PINK1-related mitophagy.
2023-05-10 | PXD039514 | Pride
Project description:Differential gene expression comparison between cortex of placebo and PSD-95 inhibitor (Tat-NR2B9c), treated cynomolgus macaques at 1 and 6 hours after middle cerebral artery occlusion. The purpose of this study was to identify changes in differential gene expression in the cortex of animals receiving strokes across the two time points and bewtwee the two treatment groups. Differential gene expression was defined as the ratio of fluroescene detected for expressed sequence tags in the left, unoperated cortex versus the contralateral, right, ischemic cortex at each time point. Two colour, Agilent, 4x44k whole genome macaca mulata microarrays with sample rna hybridized to Cy5 channel and universal macaca mulatta rna control on the Cy3 channel were obtained for each hemisphere. Comparisons between treatment groups at each time point and within in each treatment group across each time point were made to detect differential gene expression. Significant differential gene expression was defined as greater than 2-fold change and p<0.05 by T-test. Three condition experiment comparing the effect of treatment with placebo versus Tat-NR2B9c administered 5 min after MCAO with tissue samples collected 1h and 6h after MCAO and a second comparison of gene expression within each treatment group between 1h and 6h: 3 biological replicates in each group
2012-02-08 | E-GEOD-35589 | biostudies-arrayexpress
Project description:This study aims at a comprehensive understanding of the genomic program activated during early-phase of collateral vessel growth in a rat model for cerebral adaptive arteriogenesis (3-VO). While arteriogenesis constitutes a promising therapeutic concept for cerebrovascular ischemia, genomic profiles essential for therapeutic target identification were analysed solely for collateral arteries of the heart and periphery. Despite challenging anatomical conditions of the brain the 3-VO model allows identification of differentially expressed genes during adaptive cerebral arteriogenesis by selective removal of the posterior cerebral artery (PCA). Experiment Overall Design: Using an established rat model of nonischemic cerebral hypoperfusion (3-VO) (Busch, Buschmann; 2003), RNA was extracted from isolated ipsilateral PCA. Pooled RNAs from groups of intact (0h), sham and 3-VO animals 24h and 3 days after surgery, were hybridised repeatedly for an extensive genome screen of 15866 genes applying standardized Affymetrix technology. For each Array total RNA from 8 animals was processed, pooled and hybridized to a Rat230A GeneChip per group. These groups were classified as follows: intact control (N=3), 24h3VO (N=3); 24h sham (N=3), 3days3VO (N=3); and 3days sham(N=3). Hybridization, washing, antibody amplification, staining, and scanning of probe arrays were performed according to the Affymetrix Technical Manual. Probe arrays were scanned using the GeneChip System (Hewlett-Packard, Santa Cruz, CA)(Affymetrix) and raw data were processed using GCOS and normalized to a global intensity of 500.
2008-10-25 | E-GEOD-6189 | biostudies-arrayexpress
Project description:Comparing genetic differences between human and nonhuman primates is a fundamental method to dissect the molecular mechanisms underlying the improved human cognitive ability during evolution. Besides DNA sequence divergences, gene regulation differences between human and nonhuman primates have been shown to be more prominent. DNA methylation is an important type of epigenetic modification that plays critical roles in gene regulations. Trans-generational inheritances of DNA methylation in mammals are widely accepted, suggesting the evolutionary role of DNA methylation. To test if DNA methylation has contributed to the evolution of human brain, with the use of MeDIP-Chip and SEQUENOM MassARRAY, we conducted a systematic analysis to identify the differentially methylated DNA regions (DMRs) between human and rhesus macaque in the cerebral cortex. We first identified a total of 150 candidate DMRs by the MeDIP-Chip method, among which 6 DMRs were confirmed by the SEQUENOM MassARRAY method. And 4 of them were further confirmed using independent samples, while the other 2 were failed to test due to technical difficulties. All the 6 DMRs were in CpG islands or close to CpG islands, and a MIR3 repeat element was located in one DMR, but no repeats was found in the other 5 DMRs. For the 6 DMR genes, most have neural related functions, and their proteins tend to be conserved. Additionally, we found the DNA sequence changes at CpG sites contributed to the species-specific DNA methylation. Our study shed light on the researches of trans-generational epigenetic inheritance and the roles of DNA methylation in evolution, especially human evolution. Compare the DNA methylation levels between human and rhesus macaque
2012-03-01 | E-GEOD-27459 | biostudies-arrayexpress
Project description:We obtained the profiles of neuronal phosphoproteome after cerebral ischemia onset by isolating mice hippocampus. Hippocampus combined from either ten sham or ten focal cerebral ischemia 2 h mice were lysed, digested, labeled with different TMT tags, then pooled and analyzed by LC/LC-MS/MS. Five percent of the pool was used for whole proteome analysis, and the remaining 95% was subjected to phosphoproteome profiling. In total, we quantified 5,174 proteins and 9,062 phosphopeptides. Interesting, 21 proteins were upregulated and 7 proteins were downregulated in hippocampus lysates of cerebral ischemia 2 h relative to sham base on fold change. S100a9, Alpha-2-HS-glycoprotein (Ahsg), Fibrinogen beta chain (Fga) and Complement Component C3(c3) are the top significantly changed, which were highly consistent with previous reports in cerebral ischemia injury. Using wolfpsort software to analysis the Subcellular Location, 57% of detected proteins were location to extracellular, 15% were cytoplasmic protein, another 11% were transport to nucleus, and the others were location to plasma membranes (10%), mitochondria (4%) and endoplasmic reticulum (3%). Moreover,184 phosphorylation sites of 135 proteins were upregulated and 689 phosphorylation sites of 420 proteins were downregulated in hippocampus during cerebral ischemia 2 h compare with sham operation. Employing wolfpsort software analysis the subcellular location, 50% of phosphorylated proteins were location to nucleus, 26% were cytoplasmic protein, another 16% were transport to plasma membranes, and the others were location to mitochondria (4%), extracellular (3%) and cytoskeleton (1%). Motif analysis showed that 85% were belongs to serine-type phosphorylation, about 14 were threonine-type phosphorylation and 1% were tyrosine-type phosphorylation.
2022-03-14 | PXD027145 | Pride
Project description:Using data-independent acquisition-based mass spectrometry analysis, we determined the protein changes in cerebral arteries in pre- and early-onset hypertension from the spontaneously hypertensive rat (SHR), a model that resembles essential hypertension. Our analysis identified 125 proteins with expression levels that were significantly up- or downregulated in 12-week old SHRs compared to normotensive Wistar Kyoto rats. Using an angiogenesis enrichment analysis, we identified a critical imbalance in angiogenic proteins, promoting an anti-angiogenic profile in cerebral arteries at the early-onset of hypertension. In a comparison to previously published data, we demonstrate that this angiogenic imbalance is not present in mesenteric and renal arteries from age-matched SHRs. Finally, we identified two proteins (Fbln5 and Cdh13), whose expression levels were critically altered in cerebral arteries compared to the other arterial beds. The observation of an angiogenic imbalance in cerebral arteries from the SHR reveals critical protein changes in the cerebrovasculature at the early-onset of hypertension and provides novel insight into the early pathology of cerebrovascular disease.
2023-09-20 | PXD040818 | Pride