Similar Datasets
Project description:Reprogramming of adult somatic cells into induced pluripotent stem cells (iPSCs) resets the aging clock and is thought to erase other epigenomic marks. Here we show that iPSCs from late-onset sporadic Alzheimer’s disease (AD) cases retain epigenomic anomalies that supersede developmental defects, genomic instability, and neurodegeneration. When compared to iPSCs from elderly controls, AD iPSCs display reduced BMI1 and KDM5A expression, a more relax heterochromatin, and an altered DNA methylome. AD neuroepithelial cells show lesser efficient neural induction and forebrain specification, together with perturbed WNT signaling. They also present a unique genomic instability phenotype characterized by replication stress and DNA damage at the nuclear envelope-associated heterochromatin. BMI1 knockdown in control neuroepithelial cells phenocopied the AD-related pathologies. Long-term AD neuronal cultures show a dedifferentiation and loss-of-cell identity phenotype resembling epigenome erosion. BMI1 overexpression in AD neurons mitigates amyloid accumulation, tau pathology, heterochromatin fragmentation and G4 DNA induction. These findings implicate persistent epigenomic anomalies or uncharacterized genetic alterations working in trans on the epigenome in AD iPSCs, which could have broader implications in our understanding of the disease origin and pathophysiological mechanisms.
2024-07-30 | GSE255983 | GEO
Project description:Reprogramming of adult somatic cells into induced pluripotent stem cells (iPSCs) resets the aging clock and is thought to erase other epigenomic marks. Here we show that iPSCs from late-onset sporadic Alzheimer’s disease (AD) cases retain epigenomic anomalies that supersede developmental defects, genomic instability, and neurodegeneration. When compared to iPSCs from elderly controls, AD iPSCs display reduced BMI1 and KDM5A expression, a more relax heterochromatin, and an altered DNA methylome. AD neuroepithelial cells show lesser efficient neural induction and forebrain specification, together with perturbed WNT signaling. They also present a unique genomic instability phenotype characterized by replication stress and DNA damage at the nuclear envelope-associated heterochromatin. BMI1 knockdown in control neuroepithelial cells phenocopied the AD-related pathologies. Long-term AD neuronal cultures show a dedifferentiation and loss-of-cell identity phenotype resembling epigenome erosion. BMI1 overexpression in AD neurons mitigates amyloid accumulation, tau pathology, heterochromatin fragmentation and G4 DNA induction. These findings implicate persistent epigenomic anomalies or uncharacterized genetic alterations working in trans on the epigenome in AD iPSCs, which could have broader implications in our understanding of the disease origin and pathophysiological mechanisms.
2024-07-30 | GSE255982 | GEO
Project description:Reprogramming of adult somatic cells into induced pluripotent stem cells (iPSCs) resets the aging clock and is thought to erase other epigenomic marks. Here we show that iPSCs from late-onset sporadic Alzheimer’s disease (AD) cases retain epigenomic anomalies that supersede developmental defects, genomic instability, and neurodegeneration. When compared to iPSCs from elderly controls, AD iPSCs display reduced BMI1 and KDM5A expression, a more relax heterochromatin, and an altered DNA methylome. AD neuroepithelial cells show lesser efficient neural induction and forebrain specification, together with perturbed WNT signaling. They also present a unique genomic instability phenotype characterized by replication stress and DNA damage at the nuclear envelope-associated heterochromatin. BMI1 knockdown in control neuroepithelial cells phenocopied the AD-related pathologies. Long-term AD neuronal cultures show a dedifferentiation and loss-of-cell identity phenotype resembling epigenome erosion. BMI1 overexpression in AD neurons mitigates amyloid accumulation, tau pathology, heterochromatin fragmentation and G4 DNA induction. These findings implicate persistent epigenomic anomalies or uncharacterized genetic alterations working in trans on the epigenome in AD iPSCs, which could have broader implications in our understanding of the disease origin and pathophysiological mechanisms.
2024-07-30 | GSE255981 | GEO
Project description:Presenilin 1 (PSEN1) is the most frequently mutated gene in early-onset sporadic and familial Alzheimer’s disease (FAD). The PSEN1 complex displays gamma-secretase activity and promotes cleavage of the C99-terminal fragment of the Amyloid Precursor Protein (APP) into the A42 peptide. PSEN1 is also involved in vesicle transport across ER and mitochondria in so called mitochondria associated membranes. We generated induced pluripotent stem cells (iPSCs) from 5 controls and 5 FAD cases carrying the PSEN1 A246E and L286V mutations. Unexpectedly, global gene expression profile analysis of FAD iPSCs revealed profound perturbation of mitochondrial, Golgi apparatus and ER pathways. PSEN1, APP and Nicastrin were highly expressed in iPSCs and PSEN1 localized to membrane-bound organelles. FAD iPSCs grown slower and showed elevated cell death together with abnormally high A42 secretion. Mitochondrial reactive oxygen species (ROS) were elevated in FAD iPSCs and treatment with a ROS scavenger significantly improved cell death, proliferation, and DNA damage. However, it could not improve the severe ATP deficit. Inhibition of gamma-secretase activity further exacerbated the overall FAD iPSC phenotype. Cortical neurons produced from the differentiation of FAD iPSCs showed Alzheimer’s pathology and TGFb pathway hyper-activation. PSEN1-mutant iPSCs may serve as a new model to perform genome-wide genetic screens and to study FAD pathophysiology and PSEN1 cellular function.
2024-06-20 | GSE253337 | GEO
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: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
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:Our understanding of Alzheimer’s disease (AD) pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of AD. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). We reprogrammed primary fibroblasts from two patients with familial AD (both caused by a duplication of APP1, APPDp), two with sporadic AD (sAD1, 2) and two non-demented control individuals (NDCs) into iPSC lines. Neurons from differentiated cultures were FACS-purified and characterized. Purified cultures contained >90% neurons, clustered with fetal brain mRNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APPDp patients and patient sAD2 exhibited significantly higher levels of secreted Aβ1-40, phospho-tauThr231 (pTau) and active GSK3β (aGSK3β). Neurons from APPDp and sAD2 patients also accumulated large Rab5-positive early endosomes compared to controls. Treatment of purified neurons with β-secretase inhibitors, but not g-secretase inhibitors, caused significant reductions in pTau and aGSK3β levels. These results suggest a direct relationship between APP proteolytic processing, but not Aβ, in GSK3β activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial AD samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to AD, even though it can take decades for overt disease to manifest in patients. Total RNA extracted from normal hIPSCs, Alzheimer's patient derived hIPSCs, neurons differentiated from hIPSCs, fetal brain, fetal heart, fetal liver and fetal lung
2012-01-06 | E-GEOD-34879 | biostudies-arrayexpress
Project description:Multistage disease processes are often characterized by a linear relationship between the log of incidence rates and the log of age. Examples include sequences of somatic mutations, that can cause cancer, and have recently been linked with a range of non-malignant diseases. Using a Weibull distribution to model diseases that occur through an ordered sequence of stages, and another model where stages can occur in any order, we characterized the age-related onset of disease in UK Biobank data. Despite their different underlying assumptions, both models accurately described the incidence of over 450 diseases, demonstrating that multistage disease processes cannot be inferred from this data alone. The parametric models provided unique insights into age-related disease, that conventional studies of relative risks cannot. The rate at which disease risk increases with age was used to distinguish between "sporadic" diseases, with an initially low and slowly increasing risk, and "late-onset" diseases whose negligible risk when young rapidly increases with age. "Relative aging rates" were introduced to quantify how risk factors modify age-related risk, finding the effective age-at-risk of sporadic diseases is strongly modified by common risk factors. Relative aging rates are ideal for risk-stratification, allowing the identification of ages with equivalent-risk in groups with different exposures. Most importantly, our results suggest that a substantial burden of sporadic diseases can be substantially delayed or avoided by early lifestyle interventions.
| S-EPMC9308562 | biostudies-literature
Project description:An association between a rare, coding, non-synonymous SNP variant in the gene DZIP1 and Parkinson's disease was found, based on an analysis of the existing NGRC genome-wide association study dataset. The statistical analysis utilized the hypothesis-rich, targeted search unbiased assessment approach, rather than the hypothesis-free, genome-wide agnostic search paradigm. The association of DZIP1 with Parkinson's disease is discussed in the context of a Parkinson's disease stem-cell ageing theory.
| S-EPMC3277088 | biostudies-literature