Similar Datasets
Project description:Alzheimer’s disease (AD) is preceded by a long prodromal period of decades during which pathology accumulates in the brain prior to the onset of dementia. The molecular basis of these changes as well as how and when they start are unclear. Here we have analyzed neural progenitor (NP) cells and neurons generated from induced pluripotent stem cells (iPSCs) from individuals with sporadic AD (AD) and age-matched controls. Transcriptome analysis does not distinguish between iPSCs from individuals with SAD and age-matched controls, but shows major differences in iPSC-derived NP cells and neurons in gene networks related to neuronal differentiation, neurogenesis and synaptic transmission. SAD NP cells exhibit accelerated neuronal differentiation, leading to the generation of neurons with increased synapse formation and electrical excitability. Network analysis of the transcriptome implicates the transcriptional repressor REST/NRSF and two components of the polycomb repressive complex 2, SUZ12 and EZH2. Accelerated differentiation of SAD NP cells was reversed by exogenous REST expression and mimicked in normal NP cells by REST knockdown. The phenotype of accelerated neural differentiation was recapitulated in NP cells and cerebral organoids derived from gene-edited iPSC lines that express apolipoprotein E4 (APOE4), the major genetic risk factor for AD. Network analysis of the APOE4-related transcriptome again showed reduced function of REST, EZH2 and SUZ12 to be the major predicted regulatory changes. Reduced function of the REST repressor was due to reduced nuclear translocation and chromatin binding, and was associated with disruption of the nuclear membrane and lamina in SAD and APOE4 NP cells. Thus, impaired function of specific transcription factors and changes in nuclear architecture may be among the earliest events in the pathogenesis of AD.
2019-01-29 | GSE117588 | GEO
Project description:Alzheimer’s disease (AD) is preceded by a long prodromal period of decades during which pathology accumulates in the brain prior to the onset of dementia. The molecular basis of these changes as well as how and when they start are unclear. Here we have analyzed neural progenitor (NP) cells and neurons generated from induced pluripotent stem cells (iPSCs) from individuals with sporadic AD (AD) and age-matched controls. Transcriptome analysis does not distinguish between iPSCs from individuals with SAD and age-matched controls, but shows major differences in iPSC-derived NP cells and neurons in gene networks related to neuronal differentiation, neurogenesis and synaptic transmission. SAD NP cells exhibit accelerated neuronal differentiation, leading to the generation of neurons with increased synapse formation and electrical excitability. Network analysis of the transcriptome implicates the transcriptional repressor REST/NRSF and two components of the polycomb repressive complex 2, SUZ12 and EZH2. Accelerated differentiation of SAD NP cells was reversed by exogenous REST expression and mimicked in normal NP cells by REST knockdown. The phenotype of accelerated neural differentiation was recapitulated in NP cells and cerebral organoids derived from gene-edited iPSC lines that express apolipoprotein E4 (APOE4), the major genetic risk factor for AD. Network analysis of the APOE4-related transcriptome again showed reduced function of REST, EZH2 and SUZ12 to be the major predicted regulatory changes. Reduced function of the REST repressor was due to reduced nuclear translocation and chromatin binding, and was associated with disruption of the nuclear membrane and lamina in SAD and APOE4 NP cells. Thus, impaired function of specific transcription factors and changes in nuclear architecture may be among the earliest events in the pathogenesis of AD.
2019-01-29 | GSE117586 | GEO
Project description:Alzheimer’s disease (AD) is preceded by a long prodromal period of decades during which pathology accumulates in the brain prior to the onset of dementia. The molecular basis of these changes as well as how and when they start are unclear. Here we have analyzed neural progenitor (NP) cells and neurons generated from induced pluripotent stem cells (iPSCs) from individuals with sporadic AD (AD) and age-matched controls. Transcriptome analysis does not distinguish between iPSCs from individuals with SAD and age-matched controls, but shows major differences in iPSC-derived NP cells and neurons in gene networks related to neuronal differentiation, neurogenesis and synaptic transmission. SAD NP cells exhibit accelerated neuronal differentiation, leading to the generation of neurons with increased synapse formation and electrical excitability. Network analysis of the transcriptome implicates the transcriptional repressor REST/NRSF and two components of the polycomb repressive complex 2, SUZ12 and EZH2. Accelerated differentiation of SAD NP cells was reversed by exogenous REST expression and mimicked in normal NP cells by REST knockdown. The phenotype of accelerated neural differentiation was recapitulated in NP cells and cerebral organoids derived from gene-edited iPSC lines that express apolipoprotein E4 (APOE4), the major genetic risk factor for AD. Network analysis of the APOE4-related transcriptome again showed reduced function of REST, EZH2 and SUZ12 to be the major predicted regulatory changes. Reduced function of the REST repressor was due to reduced nuclear translocation and chromatin binding, and was associated with disruption of the nuclear membrane and lamina in SAD and APOE4 NP cells. Thus, impaired function of specific transcription factors and changes in nuclear architecture may be among the earliest events in the pathogenesis of AD.
2019-01-29 | GSE117585 | GEO
Project description:Alzheimer’s disease (AD) is preceded by a long prodromal period of decades during which pathology accumulates in the brain prior to the onset of dementia. The molecular basis of these changes as well as how and when they start are unclear. Here we have analyzed neural progenitor (NP) cells and neurons generated from induced pluripotent stem cells (iPSCs) from individuals with sporadic AD (AD) and age-matched controls. Transcriptome analysis does not distinguish between iPSCs from individuals with SAD and age-matched controls, but shows major differences in iPSC-derived NP cells and neurons in gene networks related to neuronal differentiation, neurogenesis and synaptic transmission. SAD NP cells exhibit accelerated neuronal differentiation, leading to the generation of neurons with increased synapse formation and electrical excitability. Network analysis of the transcriptome implicates the transcriptional repressor REST/NRSF and two components of the polycomb repressive complex 2, SUZ12 and EZH2. Accelerated differentiation of SAD NP cells was reversed by exogenous REST expression and mimicked in normal NP cells by REST knockdown. The phenotype of accelerated neural differentiation was recapitulated in NP cells and cerebral organoids derived from gene-edited iPSC lines that express apolipoprotein E4 (APOE4), the major genetic risk factor for AD. Network analysis of the APOE4-related transcriptome again showed reduced function of REST, EZH2 and SUZ12 to be the major predicted regulatory changes. Reduced function of the REST repressor was due to reduced nuclear translocation and chromatin binding, and was associated with disruption of the nuclear membrane and lamina in SAD and APOE4 NP cells. Thus, impaired function of specific transcription factors and changes in nuclear architecture may be among the earliest events in the pathogenesis of AD.
2019-01-29 | GSE117584 | GEO
Project description:REST and Neural Gene Network Dysregulation in iPS Cell Models of Alzheimer’s Disease
| PRJNA482597 | ENA
Project description:The molecular basis of the earliest neuronal changes that lead to Alzheimer's disease (AD) is unclear. Here, we analyze neural cells derived from sporadic AD (SAD), APOE4 gene-edited and control induced pluripotent stem cells (iPSCs). We observe major differences in iPSC-derived neural progenitor (NP) cells and neurons in gene networks related to neuronal differentiation, neurogenesis, and synaptic transmission. The iPSC-derived neural cells from SAD patients exhibit accelerated neural differentiation and reduced progenitor cell renewal. Moreover, a similar phenotype appears in NP cells and cerebral organoids derived from APOE4 iPSCs. Impaired function of the transcriptional repressor REST is strongly implicated in the altered transcriptome and differentiation state. SAD and APOE4 expression result in reduced REST nuclear translocation and chromatin binding, and disruption of the nuclear lamina. Thus, dysregulation of neural gene networks may set in motion the pathologic cascade that leads to AD.
| S-EPMC6386196 | biostudies-literature
Project description:Summary Nonconvulsive epileptiform activity and microglial alterations have been detected in people with Alzheimer’s disease (AD) and related mouse models. However, the relationship between these abnormalities remains to be elucidated. We suppressed epileptiform activity by treatment with the antiepileptic drug levetiracetam or by genetic ablation of tau and found that these interventions reversed or prevented aberrant microglial gene expression in brain tissues of aged human amyloid precursor protein transgenic mice, which simulate several key aspects of AD. The most robustly modulated genes included multiple factors previously implicated in AD pathogenesis, including TREM2, the hypofunction of which increases disease risk. Genetic reduction of TREM2 exacerbated epileptiform activity after mice were injected with kainate. We conclude that AD-related epileptiform activity markedly changes the molecular profile of microglia, inducing both maladaptive and adaptive alterations in their activities. Increased expression of TREM2 seems to support microglial activities that counteract this type of network dysfunction. Graphical abstract Highlights • Epileptiform activity and microglial mRNA changes in aged hAPP mice• Antiepileptic drug treatment and tau ablation reduce both abnormalities• TREM2 reduction exacerbates epileptiform activity after excitotoxin challenge• Neural network and microglial dysfunctions could form a vicious circle in AD Das et al. show that suppressing nonconvulsive epileptiform activity in an Alzheimer’s disease related mouse model reduces aberrant expression of microglial genes, including overexpression of TREM2, a strong Alzheimer risk gene in humans. Reducing TREM2 in mice exacerbated excitotoxin-induced epileptiform activity. Thus, TREM2 may help microglia curtail neural network dysfunction.
| S-EPMC8561005 | biostudies-literature
Project description:REST and Neural Gene Network Dysregulation in iPS Cell Models of Alzheimer’s Disease (Affymetrix iPSC data set)
| PRJNA482599 | ENA
Project description:REST and Neural Gene Network Dysregulation in iPS Cell Models of Alzheimer’s Disease (Affymetrix neurons data set)
| PRJNA482600 | ENA
Project description:REST and Neural Gene Network Dysregulation in iPS Cell Models of Alzheimer’s Disease (RNA-seq data set)
| PRJNA482601 | ENA