Transcriptomic and chromatin profiling of familial Alzheimer’s disease mutations in PSEN1, PSEN2, APP [RNA-seq]
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PROVIDER: PRJNA851439 | ENA |
REPOSITORIES: ENA
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Project description:Mutations in PSEN1, PSEN2, and APP cause familial Alzheimer’s Disease (FAD) with an early age at onset and progressive cognitive decline. We mechanistically characterize mutations in these three FAD genes using patient-derived neurons by integrating RNA- and ATAC-sequencing. Here, we demonstrate that FAD mutations share common disease endotypes with varying severity, particularly activation of non-ectoderm lineage and loss of neuron mitochondrial energy production, paving the way for potential therapeutic interventions.
2025-01-06 | GSE206602 | GEO
Project description:Mutations in PSEN1, PSEN2, and APP cause familial Alzheimer’s Disease (FAD) with an early age at onset and progressive cognitive decline. We mechanistically characterize mutations in these three FAD genes using patient-derived neurons by integrating RNA- and ATAC-sequencing. Here, we demonstrate that FAD mutations share common disease endotypes with varying severity, particularly activation of non-ectoderm lineage and loss of neuron mitochondrial energy production, paving the way for potential therapeutic interventions.
2025-01-06 | GSE206588 | GEO
Project description:Transcriptomic and chromatin profiling of familial Alzheimer’s disease mutations in PSEN1, PSEN2, APP
| PRJNA851445 | ENA
Project description:Transcriptomic and chromatin profiling of familial Alzheimer’s disease mutations in PSEN1, PSEN2, APP [ATAC-seq]
| PRJNA851435 | ENA
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: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: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 common form of dementia characterized by amyloid plaque deposition, TAU pathology, neuroinflammation and neurodegeneration. Mouse models recapitulate some key features of AD. For instance, the B6.APP/PS1 model (carrying human transgenes for mutant forms of APP and PSEN1) shows plaque deposition and associated neuroinflammatory responses involving both astrocytes and microglia beginning around 6 months of age. However, in our colony, TAU pathology, significant neurodegeneration and cognitive decline are not apparent in this model even at older ages. Therefore, this model is ideal for studying neuroinflammatory responses to amyloid deposition. Here, RNA sequencing of brain and retinal tissue, generalized linear modeling (GLM), functional annotation followed by validation by immunofluorescence (IF) was performed in B6.APP/PS1 mice to determine the earliest molecular changes prior to and around the onset of plaque deposition (2-6 months of age).
2019-11-25 | GSE136861 | 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