Transcriptomic profiling of sporadic Alzheimer’s disease patients
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA839035 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Alzheimer’s disease (AD) manifested before age 65 is commonly referred to as early-onset AD (EOAD). While the majority (> 90%) of EOAD cases are not caused by autosomal-dominant mutations in PSEN1, PSEN2, and APP, they do have a higher heritability (92–100%) than sporadic late-onset AD (LOAD, 70%). Although the endpoint clinicopathological changes, i.e., Aβ plaques, tau tangles, and cognitive decline, are common across EOAD and LOAD, the disease progression is highly heterogeneous. This heterogeneity, leading to temporally distinct age at onset (AAO) and stages of cognitive decline, may be caused by myriad combinations of distinct disease-associated molecular mechanisms. We and others have used transcriptome profiling in AD patient-derived neuron models of autosomal-dominant EOAD and sporadic LOAD to identify disease endotypes. Further, analyses of large postmortem brain cohorts demonstrate that only one-third of AD patients show hallmark disease endotypes like increased inflammation and decreased synaptic signaling. Areas of the brain less affected by AD pathology at early disease stages—such as the primary visual cortex—exhibit similar transcriptomic dysregulation as those regions traditionally affected and, therefore, may offer a view into the molecular mechanisms of AD without the associated inflammatory changes and gliosis induced by pathology. To this end, we analyzed AD patient samples from the primary visual cortex (19 EOAD, 20 LOAD) using transcriptomic signatures to identify patient clusters and disease endotypes. Interestingly, although the clusters showed distinct combinations and severity of endotypes, each patient cluster contained both EOAD and LOAD cases, suggesting that AAO may not directly correlate with the identity and severity of AD endotypes.
2022-10-12 | GSE203206 | 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
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: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:Modeling early-onset sporadic Alzheimer’s disease using iPSC-derived neurons
| PRJNA964438 | ENA
Project description:Modeling sporadic Alzheimer’s disease in human brain organoids under serum exposure
| PRJNA688885 | ENA
Project description:This data was divided into three experiment sets: 1. A somatic study of sporadic motor neuron disease (SMND) brain samples that were compared to the blood from the same individual, normal control brains and disease control brans (Parkinson Disease patients); 2. A twin study comparing blood and other tissue samples from twins that were discordant for MND, concordant for MND and control twins and 3. A trio study of blood samples MND patients compared to their unaffected parents. Study 1: 36 sporadic motor neuron disease brain (lateral frontal cortex, Brodmann area 46), 34 matched sporadic motor neuron disease blood, 26 control brain (lateral frontal cortex, Brodmann area 46), 9 Parkinson Disease brain (disease controls, lateral frontal cortex, Brodmann area 46). Study 2 and study 3: 52 twin or trio blood, 4 twin hair, 1 twin sperm. 2 replicate twin blood and 1 replicate trio blood repeated at a different time. External control blood from Coriell GM15510 and GM10851.
2010-07-31 | E-GEOD-15826 | biostudies-arrayexpress
Project description:Evidence suggests that extracellular vesicles (EVs) act as mediators and biomarkers of neurodegenerative diseases. Two distinct forms of Alzheimer Disease (AD) are known: a late-onset sporadic form (SAD) and an early-onset familial form (FAD). This project aims to characterize and compare the protein profile of systemic EVs from postmortem SAD and FAD patients and compared them to postmortem controls. We used LC-MS/MS label-free analysis.
2021-09-09 | PXD021718 | Pride
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:Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder that is clinically defined in terms of motor symptoms. These are preceded by prodromal non-motor manifestations that prove the systemic nature of the disease. Identifying genes and pathways altered in living patients provide new information on the diagnosis and pathogenesis of sporadic PD. We study changes in gene expression in the blood of 40 sporadic PD patients and 20 healthy controls (“Discovery set”) by taking advantage of the Affymetrix platform. Patients were at the onset of motor symptoms and before initiating any pharmacological treatment. By applying Ranking-Principal Component Analysis, PUMA and Significance Analysis of Microarrays, gene expression profiling discriminates patients from healthy controls and identifies differentially expressed genes in blood. The majority of these are also present in dopaminergic neurons of the Substantia Nigra, the key site of neurodegeneration. Together with neuronal apoptosis, lymphocyte activation and mitochondrial dysfunction, already found in previous analysis of PD blood and post-mortem brains, we unveiled transcriptome changes enriched in biological terms related to epigenetic modifications including chromatin remodeling and methylation. Candidate transcripts were validated by RT-qPCR in an independent cohort of 12 patients and controls (“Validation set”). Our data support the use of blood transcriptomics to study neurodegenerative diseases. It identifies changes in crucial components of chromatin remodeling and methylation machineries as early events in sporadic PD suggesting epigenetics as target for therapeutic intervention.
2015-10-29 | GSE72267 | GEO