Long-term caffeine treatment of Alzheimer mouse models ameliorates behavioural deficits and neuron loss and promotes cellular and molecular markers of neurogenesis
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ABSTRACT:
PROVIDER: PRJNA759924 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15707012.fastq.gz | Fastqsanger.gz | |||
| SRR15707013.fastq.gz | Fastqsanger.gz | |||
| SRR15707014.fastq.gz | Fastqsanger.gz | |||
| SRR15707015.fastq.gz | Fastqsanger.gz | |||
| SRR15707016.fastq.gz | Fastqsanger.gz |
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Project description:Epidemiological studies suggest that consumption of caffeine, the most commonly consumed psychoactive substances found in coffee, tea or soft drinks reduces the risk of developing Alzheimer’s disease (AD). While previous studies employing transgenic AD mouse models reported on reduced amyloid plaque load or an amelioration of behavioral deficits, there is only limited information on its potential effects on neurodegeneration. In the current study, we assessed whether long-term caffeine consumption affects hippocampal neuron loss and associated behavioral deficits in the Tg4-42 mouse model of AD. Treatment over a 4 months period reduced hippocampal neuron loss, rescued learning and memory deficits and ameliorates impaired neurogenesis. Neuron-specific hippocampal transcriptome analysis revealed an altered expression profile with an up-regulation of genes linked to synaptic function and processes, as well as neural progenitor proliferation. Treatment of 5xFAD mice with the same paradigm also rescued behavioral deficits, however, without affecting extracellular amyloid-beta (Abeta) levels or altered APP processing.
2021-12-13 | GSE183323 | GEO
Project description:Epidemiological studies indicate that the consumption of caffeine, the most commonly ingested psychoactive substance found in coffee, tea or soft drinks, reduces the risk of developing Alzheimer's disease (AD). Previous treatment studies with transgenic AD mouse models reported a reduced amyloid plaque load and an amelioration of behavioral deficits. It has been further shown that moderate doses of caffeine have the potential to attenuate the health burden in preclinical mouse models of a variety of brain disorders (reviewed in Cunha in J Neurochem 139:1019-1055, 2016). In the current study, we assessed whether long-term caffeine consumption affected hippocampal neuron loss and associated behavioral deficits in the Tg4-42 mouse model of AD. Treatment over a 4-month period reduced hippocampal neuron loss, rescued learning and memory deficits, and ameliorated impaired neurogenesis. Neuron-specific RNA sequencing analysis in the hippocampus revealed an altered expression profile distinguished by the up-regulation of genes linked to synaptic function and processes, and to neural progenitor proliferation. Treatment of 5xFAD mice, which develop prominent amyloid pathology, with the same paradigm also rescued behavioral deficits but did not affect extracellular amyloid-β (Aβ) levels or amyloid precursor protein (APP) processing. These findings challenge previous assumptions that caffeine is anti-amyloidogenic and indicate that the promotion of neurogenesis might play a role in its beneficial effects.
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Project description:Epigenetic Modulation to perturb the SYNGAP1 Intellectual Disability (ID) that ameliorates synaptic and behavioural deficits
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Project description:Sporadic heterozygous mutations in SYNGAP1 affect social and emotional behaviour that are often observed in intellectual disability (ID) and autism spectrum disorder (ASD). Although neurophysiological deficits have been extensively studied, the epigenetic landscape of SYNGAP1 mutation-mediated intellectual disability is unexplored. Here, we have surprisingly found that the p300/CBP specific acetylation marks of histones are significantly repressed in the adolescent hippocampus of Syngap1+/- mouse. To establish the causal relationship of Syngap1+/- phenotype and the altered histone acetylation signature we have treated 2-4 months old Syngap1+/- mouse with glucose-derived carbon nanosphere (CSP) conjugated potent small molecule activator (TTK21) of p300/CBP lysine acetyltransferase (CSP-TTK21). The enhancement of the p300/CBP specific acetylation marks of histones by CSP-TTK21 restored deficits in spine density, synaptic function, and social preferences of Syngap1+/- mouse that is very closely comparable to wild type littermates. The hippocampal RNA-Seq analysis of the treated mice revealed that the expression of many critical genes related to the ID/ASD reversed due to the treatment of the specific small molecule activator. This study could be the first demonstration of the reversal of autistic behaviour and neural wiring upon the modulation of altered epigenetic modification (s).
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Project description:Our previous research demonstrated that caffeine exposure on embryonic day (E) 8.5 increased body weight, altered cardiac morphology and function in adult male mice. However, these adverse effects were not observed in adenosine A1 receptor knockout (A1AR-/-) mice. Our hypothesis is that A1AR action mediates changes in DNA methylation patterns in mice exposed in utero to caffeine and that these changes in methylation lead to long-term effects in adult mice. To test this hypothesis, DNA Methylation 2.1M Deluxe Promoter Arrays (NimbleGen) were used to examine the methylation patterns of DNA isolated from adult left ventricles of the A1AR knockout line exposed to 20 mg/kg caffeine at E8.5 in utero. In A1AR+/+ mice, 4,896 hypermethylated and 2,823 hypomethylated regions were discovered in the left ventricles of the caffeine group compared to the normal saline group. In A1AR-/- mice, 1,024 hypermethylated and 1,757 hypomethylated regions were found in the caffeine group. The differentially methylated regions (DMRs) in the caffeine treated A1AR+/+ hearts mapped to 6,148 genes, 4,853 promoters, 4,111 primary transcripts, 816 CpG islands, and 98 miRNAs. Functional annotation clustering of genes revealed that many genes were involved in the development of hypertrophic cardiomyopathy and other heart diseases, which may explain our earlier findings of thickening of the left ventricular wall after in utero caffeine treatment. The methylation changes in several DMRs, mef2c, ins2, tnnt2, and myh6, were validated by bisulfite sequencing. In summary, in utero caffeine exposure caused DNA methylation changes in adult left ventricles and that these changes may be mediated by A1ARs. Pregnant mice were injected at embryonic day 8.5 with 0.9% NaCl (vehicle) or 20 mg/kg caffeine in vehicle i.p. Pups were born and raised until 8-10 weeks of age. Analysis was performed on the following groups vehicle A1AR+/+ (veh+/+), vehicle A1AR-/- (veh-/-), caffeine A1AR+/+ (caff+/+), and caffeine A1AR-/- (caff-/-). Genomic DNA from left ventricles of adult male mice was used. Two biological replicates were measured for each group.
2015-12-19 | E-GEOD-43030 | biostudies-arrayexpress
Project description:Genetic variants in gene regulatory sequences can modify gene expression and mediate the molecular response to environmental stimuli. In addition, genotype–environment interactions (GxE) contribute to complex traits such as cardiovascular disease. Caffeine is the most widely consumed stimulant and is known to produce a vascular response. To investigate GxE for caffeine, we treated vascular endothelial cells with caffeine and used a massively parallel reporter assay to measure allelic effects on gene regulation for over 43,000 genetic variants. We identified 665 variants with allelic effects on gene regulation and 6 variants that regulate the gene expression response to caffeine (GxE, false discovery rate [FDR] < 5%). When overlapping our GxE results with expression quantitative trait loci colocalized with coronary artery disease and hypertension, we dissected their regulatory mechanisms and showed a modulatory role for caffeine. Our results demonstrate that massively parallel reporter assay is a powerful approach to identify and molecularly characterize GxE in the specific context of caffeine consumption.
2024-02-26 | GSE221514 | GEO
Project description:To screen for xenobiotic-metabolizing-enzyme genes (XME) induced by caffeine exposure, a microarray experiment (performed with a Drosophila pangenomic array (Agilent 4 X 44K) was carried out between control and individuals exposed to caffeine (18mM ). Among 23401 genes consistantly found in the three biological replicates, 13108 showed a significant variation. 749 genes were over-expressed whereas 1518 were under-expressed. Interestingly, several genes belonging to all major classes of detoxification enzymes including XME were among the most highly induced such as CYP12d1, CYP6a8 and CYP6d5. Caffeine ingestion induced gene expression in Drosophila melanogaster male thorax and abdomen was mesured at 12h after exposure to doses of 0, 18mM of caffeine. Three independant experiments were performed at each dose using different drosophila for each experiment.
2014-07-04 | E-GEOD-59084 | biostudies-arrayexpress
Project description:Proteasomes hydrolyze most intracellular proteins. Immunoproteasome is a specific form of proteasome implicated in inflammation, cancer and autoimmune diseases. Modulation of immunoproteasome activity and content is a promising direction for the management of socially important pathologies. Using previously obtained reporter colorectal cancer cell lines, we tested how various commonly used compounds including ibuprofen, acetylsalicylic acid, vitamin C, caffeine and others, affect immunoproteasome expression. Methods: Immunoproteasome subunit expression was assessed by flow cytometry, qPCR and Western blot. Proteasome activity was tested using fluorogenic substrates and the activity probe. Transcriptome analysis was performed to identify patterns of gene expression changes. Results: Among the tested compounds caffeine was the only drug that revealed modest reduction in quantity of immunoproteasomes. The effect of caffeine on immunoproteasomes varied between cell lines and was stronger as a result of prolonged treatment. The reduction of immunoproteasome content in cells treated with caffeine coincided with decreased expression of immunoproteasome subunits and downregulation of Nrf3 transcription factor and a PAC4 proteasome assembly chaperone. Moreover, decreased expression of immunoproteasome subunits in cells treated with caffeine coincided with the reduction of oxidative stress levels. Caffeine did not affect the degradation of immunoproteasomes by autophagy. Conclusions: Modulation of immunoproteasome expression by caffeine might help to optimize existing and develop novel strategies for the treatment of colorectal cancer and several autoimmune diseases.
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Project description:Despite the diverse genetic origins of autism spectrum disorders (ASDs), affected individuals share strikingly similar and correlated behavioural traits that include perceptual and sensory processing challenges. Notably, the severity of these sensory symptoms is often predictive of the expression of other autistic traits. However, the origin of these perceptual deficits remains largely elusive. Here, we show a recurrent impairment in visual threat perception that is similarly impaired in three independent models of ASD with different molecular aetiologies. Interestingly, this deficit is associated with reduced avoidance of threatening environments - a non-perceptual trait. Focusing on a common cause of ASDs, the Setd5 gene mutation, we define the molecular mechanism. We show that the perceptual impairment is caused by a potassium channel (Kv1) mediated hypoexcitability in a subcortical node essential for the initiation of escape responses, the dorsal periaqueductal grey (dPAG). Proteomic profiling of tissue samples across different brain regions didn't show a perturbation in Kv1 levels in mutant mice. Targeted pharmacological Kv1 blockade rescued both perceptual and place avoidance deficits, causally linking seemingly unrelated trait deficits to the dPAG. Furthermore, we show that different molecular mechanisms converge on similar behavioural phenotypes by demonstrating that the autism models Cul3 and Ptchd1, despite having similar behavioural phenotypes, differ in their functional and molecular alteration. Our findings reveal a link between rapid perception controlled by subcortical pathways and appropriate learned interactions with the environment, and define a non-developmental source of such deficits in ASD.
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