Genome-wide H3K27ac profiles in post-mortem entorhinal cortex samples from Alzheimer's disease cases and controls
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE102538 | GEO | 2018/08/11
REPOSITORIES: GEO
Similar Datasets
Project description:Alzheimer’s disease (AD) is the most common neurodegenerative dementia. Around 10% of cases present an age of onset before 65 years-old, which in turn can be divided in monogenic or familial AD (FAD) and sporadic early-onset AD (EOAD). Mutations in PSEN1, PSEN2 and APP genes have been linked with FAD. The aim of our study was to describe the brain whole-genome RNA expression profile of the posterior cingulate area in EOAD and FAD caused by PSEN1 mutations (FAD-PSEN1). 14 patients (7 EOAD and 7 FAD-PSEN1) and 7 neurologically healthy controls were selected and samples were hybridized in a Human Gene 1.1 microarray from Affymetrix. When comparing controls with EOAD and controls with FAD-PSEN1, we found 3183 and 3351 differentially expressed genes (DEG) respectively (FDR corrected p<0.05). However, any DEG was found in the comparison of the two groups of patients. Microarrays were validated through quantitative-PCR of 17 DEG. In silico analysis of the DEG revealed an alteration in biological pathways related to calcium-signaling, axon guidance and long-term potentiation (LTP), among others, in both groups of patients. These pathways are mainly related with cell signalling cascades, synaptic plasticity and learning and memory processes. In conclusion, the altered biological final pathways in EOAD and FAD-PSEN1 are highly coincident. Also, the findings are in line with those previously reported for late-onset AD (LOAD, onset >65 years-old), which implies that the consequences of the disease at the molecular level are similar in the final stages of the disease. 21 Samples were analyzed: 7 controls, 7 Early-onset Alzheimer's disease (AD) patients and 7 early-onset AD genetically determined by a mutation in PSEN1 gene.
2015-01-20 | E-GEOD-39420 | biostudies-arrayexpress
Project description:Alzheimer’s disease (AD) is the most common neurodegenerative dementia. Around 10% of cases present an age of onset before 65 years-old, which in turn can be divided in monogenic or familial AD (FAD) and sporadic early-onset AD (EOAD). Mutations in PSEN1, PSEN2 and APP genes have been linked with FAD. The aim of our study was to describe the brain whole-genome RNA expression profile of the posterior cingulate area in EOAD and FAD caused by PSEN1 mutations (FAD-PSEN1). 14 patients (7 EOAD and 7 FAD-PSEN1) and 7 neurologically healthy controls were selected and samples were hybridized in a Human Gene 1.1 microarray from Affymetrix. When comparing controls with EOAD and controls with FAD-PSEN1, we found 3183 and 3351 differentially expressed genes (DEG) respectively (FDR corrected p<0.05). However, any DEG was found in the comparison of the two groups of patients. Microarrays were validated through quantitative-PCR of 17 DEG. In silico analysis of the DEG revealed an alteration in biological pathways related to calcium-signaling, axon guidance and long-term potentiation (LTP), among others, in both groups of patients. These pathways are mainly related with cell signalling cascades, synaptic plasticity and learning and memory processes. In conclusion, the altered biological final pathways in EOAD and FAD-PSEN1 are highly coincident. Also, the findings are in line with those previously reported for late-onset AD (LOAD, onset >65 years-old), which implies that the consequences of the disease at the molecular level are similar in the final stages of the disease.
2015-01-20 | GSE39420 | GEO
Project description:Induced pluripotent stem cell (iPSC) disease models have been generated for a number of diseases, and some have shown their potential utilization for pathological and drug toxicological evaluations. We have generated two hiPSC clones from a non-familial Alzheimerâs patient (AD-iPSCs), which expressed typical undifferentiated markers and fulfilled standard pluripotency assays. Genome-wide microarray analysis revealed that AD-iPSCs are highly similar to control hiPSCs and hESCs, albeit with some noticeable differences in several genes: DNAJC15, GRPR, NAIP and SNORD116-18. Several other biomarkers were differentially expressed in AD-iPSC clones, which were implicated in memory impairment and AD. Furthermore, well characterized familial AD-associated genes (APP, PSEN1, PSEN2) and non-familial (A2M, APOE, GAP43, MAOA, MPO, PLAT, PLAU, SORL1, SNCA) exhibited different expression patterns but were largely reset upon reprogramming into a pluripotent state. Overall, hiPSCs can be good candidates for AD modeling and may represent an in vitro alternative to studying disease mechanisms and drug discovery/toxicology studies. Fibroblasts and two hiPSC clones from a non-familial Alzheimerâs patient (AD-iPSCs) were analyzed. For each cell sample, 2-3 biological replicates were obtained.
2015-12-31 | E-GEOD-31163 | biostudies-arrayexpress
Project description:Type 2 diabetes mellitus (T2DM) is an independent risk factor of Alzheimer's disease (AD), thus, identifying who among the increasing T2DM populations may develop into AD is important for early intervention. By using TMT-labeling coupled high-throughput mass spectrometry, we conducted a comprehensive plasma proteomic analysis in none-T2DM people (Ctrl, n=30), and the age-/sex-matched T2DM patients with mild cognitive impairment (T2DM-MCI, n=30) or T2DM without MCI (T2DM-nMCI, n=25). The candidate biomarkers identified by proteomics and bioinformatics analyses were verified by ELISA, and their diagnostic capabilities were evaluated with machine learning. A total of 53 differentially expressed proteins (DEPs) were identified in T2DM-MCI compared with T2DM-nMCI patients. These DEPs were significantly enriched in multiple biological processes, such as amyloid neuropathies, CNS disorders, and metabolic acidosis. Among the DEPs, alpha-1-antitrypsin (SERPINA1), major viral protein (PRNP), valosin-containing protein (VCP) showed strong collection with AD high-risk genes APP, MAPT, APOE, PSEN1, and PSEN2. And the levels of PP2A cancer inhibitor (CIP2A), PRNP, corticotropin releasing factor binding protein (CRHBP) were significantly increased, while the level of VCP was decreased in T2DM-MCI patients compared with the T2DM-nMCI, and these changes were correlated with the mini-mental state examination (MMSE) score. Further machine learning data showed that increases of CIP2A, ratio of β-amyloid (rAβ42/40), and rGSK-3β(T/S9) (ratio of total to serine-9-phosphorylated glycogen synthase kinase-3β) had the greatest power to identify mild cognitive decline in T2DM patients.
2023-03-11 | PXD027870 | Pride
Project description:Background: Widescale evidence points to the involvement of glia and immune pathways in the progression of Alzheimer’s disease (AD). AD-associated iPSC-derived glial cells show a diverse range of AD-related phenotypic states encompassing cytokine/chemokine release, phagocytosis and morphological profiles, but to date studies are limited to cells derived from PSEN1, APOE and APP mutations or sporadic patients. The aim of the current study was to successfully differentiate iPSC-derived microglia and astrocytes from patients harbouring an AD-causative PSEN2 (N141I) mutation and characterise the inflammatory and morphological profile of these cells. Methods: iPSCs from three healthy control individuals and three familial AD patients harbouring a heterozygous PSEN2 (N141I) mutation were used to derive astrocytes and microglia-like cells and cell identity and morphology were characterised through immunofluorescent microscopy. Cellular characterisation involved the stimulation of these cells by LPS and Aβ42 and analysis of cytokine/chemokine release was conducted through ELISAs and multi-cytokine arrays. The phagocytic capacity of these cells was then indexed by the uptake of fluorescently labelled fibrillar Aβ42. Results: AD-derived astrocytes and microglia-like cells exhibited an atrophied and less complex morphological appearance than healthy controls. AD-derived astrocytes showed increased basal expression of GFAP, S100β and increased secretion and phagocytosis of Aβ42 while AD-derived microglia-like cells showed decreased IL-8 secretion compared to healthy controls. Upon immunological challenge AD-derived astrocytes and microglia-like cells show exaggerated secretion of the pro-inflammatory IL-6, CXCL1, ICAM-1 and IL-8 from astrocytes and IL-18 and MIF from microglia.Conclusion: Our study showed, for the first time, the differentiation and characterisation of iPSC-derived astrocytes and microglia-like cells harbouring a PSEN2 (N141I) mutation. PSEN2 (N141I)-mutant astrocytes and microglia-like cells presented with a ‘primed’ phenotype characterised by reduced morphological complexity, exaggerated pro-inflammatory cytokine secretion and altered Aβ42 production and phagocytosis.
2024-01-07 | GSE243177 | GEO
Project description:Induced pluripotent stem cell (iPSC) disease models have been generated for a number of diseases, and some have shown their potential utilization for pathological and drug toxicological evaluations. We have generated two hiPSC clones from a non-familial Alzheimer’s patient (AD-iPSCs), which expressed typical undifferentiated markers and fulfilled standard pluripotency assays. Genome-wide microarray analysis revealed that AD-iPSCs are highly similar to control hiPSCs and hESCs, albeit with some noticeable differences in several genes: DNAJC15, GRPR, NAIP and SNORD116-18. Several other biomarkers were differentially expressed in AD-iPSC clones, which were implicated in memory impairment and AD. Furthermore, well characterized familial AD-associated genes (APP, PSEN1, PSEN2) and non-familial (A2M, APOE, GAP43, MAOA, MPO, PLAT, PLAU, SORL1, SNCA) exhibited different expression patterns but were largely reset upon reprogramming into a pluripotent state. Overall, hiPSCs can be good candidates for AD modeling and may represent an in vitro alternative to studying disease mechanisms and drug discovery/toxicology studies.
2015-12-31 | GSE31163 | GEO
Project description:PRESENILIN 2 (PSEN2) is one of the genes mutated in early onset familial Alzheimer’s disease (EOfAD). PSEN2 shares significant amino acid sequence identity with another EOfAD-related gene PRESENILIN 1 (PSEN1), and partial functional redundancy is seen between these two genes. However, the complete range of functions of PSEN1 and PSEN2 is not yet understood. In this study, we performed targeted mutagenesis of the zebrafish psen2 gene to generate a premature termination codon close downstream of the translation start with the intention of creating a null mutation. Homozygotes for this mutation, psen2S4Ter, are viable and fertile, and adults do not show any gross pigmentation defects, arguing against significant loss of γ-secretase activity. Transcripts containing the S4Ter mutation do not appear to be destabilized by nonsense-mediated decay. Forced expression in zebrafish embryos of fusions of psen2S4Ter 5’ mRNA sequences with sequence encoding green fluorescent protein (GFP) indicated that the psen2S4Ter mutation permits utilization of cryptic, novel downstream translation start codons. These likely initiate translation of N-terminally truncated Psen2 proteins that obey the “reading frame preservation rule” of PRESENILIN EOfAD mutations. Transcriptome analysis of entire brains from a 6-month-old family of wild type, heterozygous and homozygous psen2S4Ter female siblings revealed profoundly dominant effects on gene expression likely indicating changes in mitochondrial and (possibly) ribosomal function.
2020-04-11 | GSE148468 | GEO
Project description:Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most frequent cause of dementia. The disease has a substantial genetic component comprising both highly penetrant familial mutations (APP, PSEN1 and PSEN2) and sporadic cases with complex genetic etiology. Mutations in APP and PSEN1/2 alter the proteolytic processing of APP to its metabolites, including Ab and APP Intracellular Domain (AICD). In this study, we use transgenic porcine models carrying the human APPsw and PSEN1M146I transgenes to demonstrate the pathobiological relevance of transcriptional regulation facilitated by APP and its AICD domain. Through molecular characterization of hippocampal tissue, we describe the differential expression of gene sets that cluster in molecular pathways with translational relevance to AD. We further identify phosphorylated and unphosphorylated AICD in differential complexes with proteins implicated in signal transduction and transcriptional regulation. Integrative genomic analysis of transcriptional changes in somatic cell cultures derived from pigs treated with g-secretase inhibitor demonstrates the importance of g-secretase APP processing in transcriptional regulation. Collectively, our data supports a model in which APP, and in particular its AICD domain, modulates gene networks associated with AD pathobiology through interaction with signaling proteins.
2024-02-04 | GSE254570 | GEO
Project description:Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most frequent cause of dementia. The disease has a substantial genetic component comprising both highly penetrant familial mutations (APP, PSEN1 and PSEN2) and sporadic cases with complex genetic etiology. Mutations in APP and PSEN1/2 alter the proteolytic processing of APP to its metabolites, including Ab and APP Intracellular Domain (AICD). In this study, we use transgenic porcine models carrying the human APPsw and PSEN1M146I transgenes to demonstrate the pathobiological relevance of transcriptional regulation facilitated by APP and its AICD domain. Through molecular characterization of hippocampal tissue, we describe the differential expression of gene sets that cluster in molecular pathways with translational relevance to AD. We further identify phosphorylated and unphosphorylated AICD in differential complexes with proteins implicated in signal transduction and transcriptional regulation. Integrative genomic analysis of transcriptional changes in somatic cell cultures derived from pigs treated with g-secretase inhibitor demonstrates the importance of g-secretase APP processing in transcriptional regulation. Collectively, our data supports a model in which APP, and in particular its AICD domain, modulates gene networks associated with AD pathobiology through interaction with signaling proteins.
2024-02-04 | GSE254548 | GEO
Project description:Non-familial Alzheimer’s disease (AD) occurring before 65 years of age is commonly referred to as early-onset Alzheimer’s disease (EOAD) and constitutes ~5-6% of all Alzheimer’s disease (AD) cases. While EOAD exhibits the same clinicopathological changes such as amyloid plaques, neurofibrillary tangles (NFTs), brain atrophy, and cognitive decline as observed in the more prevalent late-onset AD (LOAD), EOAD patients tend to have more severe cognitive deficits, including visuospatial, language, and motor dysfunction. Patient-derived induced pluripotent stem cells (iPSCs) have been used to model and study penetrative, familial AD (FAD) mutations in APP, PSEN1, and PSEN2, but have been seldom used for sporadic forms of AD that display more heterogeneous disease manifestation. In this study, we sought to characterize iPSC-derived neurons from EOAD patients via RNA-sequencing. A modest difference in expression profiles between EOAD patients and non-demented control subjects resulted in a limited number of differentially expressed genes (DEGs). Based on this analysis, we provide evidence that iPSC-derived neuron model systems, likely due to the loss of EOAD-associated epigenetic signatures during the iPSC reprogramming, are not an ideal model system to study sporadic AD.
2023-11-21 | GSE231341 | GEO