Up-regulation of adenosine receptors in the frontal cortex in Alzheimer's disease.
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ABSTRACT:
SUBMITTER: Albasanz JL
PROVIDER: S-EPMC8095610 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by intracellular formation of neurofibrillary tangles and extracellular deposition of β-amyloid protein (Aβ) in the extracellular matrix. The pathogenesis of AD has not yet been fully elucidated and little is known about global alterations in the brain proteome that are related to AD. To identify and quantify such AD-related changes in the brain, we employed a tandem mass tags approach coupled to high-resolution mass spectrometry. We compared the proteomes of frontal cortex from AD patients with corresponding age-matched brain samples. Liquid chromatography-mass spectrometry/MS analysis carried out on an Orbitrap Fusion Lumos Tribrid mass spectrometer led to identification of 8,066 proteins. Of these, 432 proteins were observed to be significantly altered (>1.5 fold) in their expression in AD brains. Proteins whose abundance was previously known to be altered in AD were identified including secreted phosphoprotein 1 (SPP1), somatostatin (SST), SPARC-related modular calcium binding 1 (SMOC1), dual specificity phosphatase 26 (DUSP26), and neuronal pentraxin 2 (NPTX2). In addition, we identified several novel candidates whose association with AD has not been previously described. Of the novel molecules, we validated chromogranin A (CHGA), inner membrane mitochondrial protein (IMMT) and RAS like proto-oncogene A (RALA) in an additional set of 20 independent brain samples using targeted parallel reaction monitoring mass spectrometry assays. The differentially expressed proteins discovered in our study, once validated in larger cohorts, should help discern the pathogenesis of AD.
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Project description:There is accumulating evidence that amyloid beta and tau proteins may act synergistically to cause synapse and neural circuit degeneration in Alzheimer’s disease. In order to study this, we designed a new mouse model which lacks endogenous mouse tau, but expresses both the APP/PS1 transgene, which causes well-characterised plaque-associated synapse loss, and also reversibly expresses wild-type human tau (which can be suppressed with doxycycline). We examined the transcriptional changes in the frontal cortex of this mouse model, along with behaviour, pathology, synaptic plasticity, synapse degeneration and accumulation of amyloid beta and tau at synapses, and compared with littermate control genotypes: those lacking endogenous mouse tau, those lacking endogenous mouse tau but expressing the APP/PS1 transgene only, and those lacking endogenous mouse tau but reversibly expressing wild-type human tau only.
2019-11-12 | E-MTAB-7856 | biostudies-arrayexpress
Project description:The adenosine hypothesis of schizophrenia posits that reduced availability of the neuromodulator adenosine contributes to dysregulation of dopamine and glutamate transmission and the symptoms associated with schizophrenia. It has been proposed that increased expression of the enzyme adenosine kinase (ADK) may drive hypofunction of the adenosine system. While animal models of ADK overexpression support such a role for altered ADK, the expression of ADK in schizophrenia has yet to be examined. In this study, we assayed ADK gene and protein expression in frontocortical tissue from schizophrenia subjects. In the dorsolateral prefrontal cortex (DLPFC), ADK-long and -short splice variant expression was not significantly altered in schizophrenia compared to controls. There was also no significant difference in ADK splice variant expression in the frontal cortex of rats treated chronically with haloperidol-decanoate, in a study to identify the effect of antipsychotics on ADK gene expression. ADK protein expression was not significantly altered in the DLPFC or anterior cingulate cortex (ACC). There was no significant effect of antipsychotic medication on ADK protein expression in the DLPFC or ACC. Overall, our results suggest that increased ADK expression does not contribute to hypofunction of the adenosine system in schizophrenia and that alternative mechanisms are involved in dysregulation of this system in schizophrenia.
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Project description:Alzheimer's disease (AD) and bipolar disorder (BD) are progressive brain disorders. Upregulated mRNA and protein levels of neuroinflammatory and arachidonic acid (AA) markers with loss of synaptic markers (synaptophysin and drebrin) have been reported in brain tissue from AD and BD patients. We hypothesized that some of these changes are associated with epigenetic modifications of relevant genes. To test this, we measured gene-specific CpG methylation, global DNA methylation and histone modifications in postmortem frontal cortex from BD (n=10) and AD (n=10) patients and respective age-matched controls (10 per group). AD and BD brains showed several epigenetic similarities, including global DNA hypermethylation, and histone H3 phosphorylation. These changes were associated with hypo- and hypermethylation of CpG islands in cyclooxygenase-2 and brain-derived neurotrophic factor promoter regions, respectively. Only the AD brain showed hyper- and hypomethylated CpG islands in promoter regions for cAMP response element-binding protein and nuclear transcription factor kappa B genes, respectively. Only the BD brain demonstrated increased global histone H3 acetylation and hypermethylation of the promotor region for the drebrin-like protein gene. There was no significant epigenetic modification for 12-lipooxygenase or p450 epoxygenase in either illness. Many observed epigenetic changes were inversely related to respective changes in mRNA and protein levels. These epigenetic modifications involving neuroinflammatory, AA cascade and synaptic markers may contribute to progression in AD and BD and identify new targets for drug development.
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Project description:Ion channel splice array data from temporal cortex brain tissue samples collected from Alzheimer's disease patients. Temporal cortex (Alzheimer's disease affected brain tissue structure) and cerebellum (Alzheimer's disease unaffected brain tissue structure) samples from control subjects were compared to temporal cortex and cerebellum of patients with Alzheimer's disease.
2010-06-11 | E-GEOD-6775 | biostudies-arrayexpress
Project description:BACKGROUND:Alzheimer's disease (AD) is the sixth leading cause of death and the most costly disease in the US. Despite the enormous impact of AD, there are no treatments that delay onset or stop disease progression currently on the market. This is partly due to the complexity of the disease and the largely unknown pathogenesis of sporadic AD, which accounts for the vast majority of cases. Epigenetics has been implicated as a critical component to AD pathology and a potential "hot spot" for treatments. Histone post-translational modifications (PTMs) are a key element in epigenetic regulation of gene expression and are known to be associated with the pathology of numerous diseases. Investigation of histone PTMs can help elucidate AD pathology and identify targets for therapies. RESULTS:A multiple reaction monitoring mass spectrometry assay was used to measure changes in abundance of several histone PTMs in frontal cortex from human donors affected with AD (n = 6) and age-matched, normal donors (n = 6). Of the changes observed, notable decreases in methylation of H2B residue K108 by 25 % and H4 residue R55 by 35 % were measured and are likely associated with hydrogen bonding networks important for nucleosome stability. Additionally, a 91 % increase in ubiquitination of K120 on H2B was measured as well as an apparent loss in acetylation of the region near the N-terminus of H4. Our method of quantification was also determined to be precise and robust, signifying measured changes were representative of true biological differences between donors and sample groups. CONCLUSION:We are the first to report changes in methylation of H2B K108, methylation of H4 R55, and ubiquitination of H2B K120 in frontal cortex from human donors with AD. These notable PTM changes may be of great importance in elucidating the epigenetic mechanism of AD as it relates to disease pathology. Beyond the structural and functional impacts of the changes we have measured, the sites of altered PTMs may be used to identify enzymes responsible for their modulation, which could be used as prospective drug targets for highly specific AD therapies.
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Project description:Mechanisms of Alzheimer's disease (AD) and its putative prodromal stage, amnestic mild cognitive impairment (aMCI), involve the dysregulation of multiple candidate molecular pathways that drive selective cellular vulnerability in cognitive brain regions. However, the spatiotemporal overlap of markers for pathway dysregulation in different brain regions and cell types presents a challenge for pinpointing causal versus epiphenomenal changes characterizing disease progression. To approach this problem, we performed Weighted Gene Co-expression Network Analysis and STRING interactome analysis of gene expression patterns quantified in frontal cortex samples (Brodmann area 10) from subjects who died with a clinical diagnosis of no cognitive impairment, aMCI, or mild/moderate AD. Frontal cortex was chosen due to the relatively protracted involvement of this region in AD, which might reveal pathways associated with disease onset. A co-expressed network correlating with clinical diagnosis was functionally associated with insulin signaling, with insulin (INS) being the most highly connected gene within the network. Co-expressed networks correlating with neuropathological diagnostic criteria (e.g., NIA-Reagan Likelihood of AD) were associated with platelet-endothelium-leucocyte cell adhesion pathways and hypoxia-oxidative stress. Dysregulation of these functional pathways may represent incipient alterations impacting disease progression and the clinical presentation of aMCI and AD.
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Project description:Ion channel splice array data from temporal cortex brain tissue samples collected from Alzheimer's disease patients. Keywords: disease associated splicing changes
2007-01-23 | GSE6775 | GEO
Project description:We initiated the systematic profiling of the dorsolateral prefrontal cortex obtained from a subset of autopsied individuals enrolled in the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP), which are jointly designed prospective studies of aging and dementia with detailed, longitudinal cognitive phenotyping during life and a quantitative, structured neuropathologic examination after death. They include over 3,322 subjects. Here, we outline the first generation of data including genome-wide genotypes (n=2,090), whole genome sequencing (n=1,179), DNA methylation (n=740), chromatin immunoprecipitation with sequencing using an anti-Histone 3 Lysine 9 acetylation (H3K9Ac) antibody (n=712), RNA sequencing (n=638), and miRNA profile (n=702). Generation of other omic data including ATACseq, proteomic and metabolomics profiles is ongoing. Thanks to its prospective design and recruitment of older, non-demented individuals, these data can be repurposed to investigate a large number of syndromic and quantitative neuroscience phenotypes. The many subjects that are cognitively non-impaired at death also offer insights into the biology of the human brain in older non-impaired individuals.
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Project description:Environmental enrichment (EE) is widely used in the life sciences to study effects of environment on the brain. In pigs, despite lack of EE being a key welfare issue there is little understanding of brain effects of EE in pigs. This project aimed to study the effects of exposure to an EE arena on piglet behaviours and on brain gene expression levels with a focus on IGF-1 and related genes. Eight litters of large white×landrace×Hampshire piglets were farrowed and raised in a free farrowing system (PigSAFE). At 42days of age, 6pigletsperlitter were given access to an enriched arena with plentiful peat, straw and space, (in groups of 4 made up of stable pairs) for 15min per day on 5 consecutive days to allow them to habituate to the apparatus. Piglet behaviours were recorded in the arena for 15min periods on 3 consecutive days. On the final day only one pair of test piglets per litter was given access to the arena. Brain tissue was collected within 45min of the test from piglets exposed to the arena on the day and their non-exposed littermate controls. RNA was extracted from the frontal cortex and QRT-PCR for selected genes run on a Stratgene MX3005P. In both the home pen and the EE arena litters spent the largest proportion of time engaging in foraging behaviour which was significantly increased in the enriched arena (t7=5.35, df=6, p=0.001). There were decreases in non-running play (t7=4.82, p=0.002) and inactivity (t7=4.6, p=0.002) in the arena. A significant fold change increase (FC=1.07, t=4.42, p=0.002) was observed in IGF-1 gene expression in the frontal cortex of piglets exposed to the enriched arena compared to those not exposed on the day of culling. No change in expression was observed in CSF1, the IGF-1 receptor gene nor in any of the binding proteins tested (IGFBP1-6). There was a weak tendency for increased expression of the neurotrophic factor BDNF1 (fold change: 1.03; t7=1.54, p=0.1). We believe this work is the first to explore effects of EE on pig brain physiology and development, and also points to a potential role for IGF-1 in brain effects of EE.
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