The transcriptomic landscape of glutamatergic cortical neurons carrying Alzheimer’s disease PSEN1 mutations reveals alterations in structural components, signalling, and ncRNA regulation
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE211993 | GEO | 2023/01/24
REPOSITORIES: GEO
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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:Lysosomal dysfunction is considered pathogenic in Alzheimer Disease (AD). Loss of Presenilin-1(PSEN1) function causing early onset AD impedes acidification via defective vATPase V0a1 subunit delivery to lysosomes. We report that isoproterenol and related β2-adrenergic agonists re-acidify lysosomes in PSEN1 KO cells and fibroblasts from PSEN1 familial AD(FAD) patients, restores lysosomal calcium homeostasis and proteolysis, and reverses impaired autophagy flux. We identify a novel rescue mechanism involving PKA-mediated facilitated delivery of ClC-7 to lysosomes, which stimulates chloride influx and reverses markedly lowered Cl- content of PSEN1 KO lysosomes. Notably, PSEN1 loss-of-function impedes ER-to-lysosome delivery of ClC-7, thus accounting for lysosomal Cl- deficits that compound pH deficits due to deficient vATPase function. Transcriptomics of PSEN1-deficient cells reveal strongly down-regulated ER-to-lysosome transport pathways and reversibility by isoproterenol. Our findings uncover a broadened PSEN1 role in lysosomal ion homeostasis and novel pH modulation of lysosomes through β-adrenergic regulation of ClC-7, which can be therapeutically modulated.
2020-02-29 | GSE136894 | GEO
Project description:Chemical Checker (CC) is a resource that provides processed, harmonized and integrated bioactivity data on 800,000 small molecules. In the CC, bioactivity data are expressed in a vector format, which naturally extends the notion of chemical similarity between compounds to similarities between bioactivity signatures of different kinds. We experimentally validate that CC signatures can be used to reverse and mimic biological signatures of disease models and genetic perturbations. We developed cellular models of Alzheimer’s disease (AD) by introducing familial AD (fAD) mutations into SH-SY5Y cells. Using CRISPR/Cas9-induced homology-directed repair, we obtained clones harboring the fAD PSEN1-M146V or the APP-V717F mutations. Three compounds (noscapine - 10 uM, palbociclib - 0.4 uM and AG-494 - 10uM) reverted fAD signatures. We confirmed that genes up-regulated in SH-SY5Y fAD mutants were indeed downregulated upon treatment with the drugs, and vice versa. Moreover, the three drug treatments significantly reverted a subset of genes strongly linked to AD, including the recovery of the expression levels of GRIN2D, a glutamate receptor involved in synaptic transmission and BIN1, a gene involved in synaptic vesicle endocytosis and strongly associated with AD risk.
2020-03-17 | GSE137202 | GEO
Project description:Alzheimer’s disease is the most common form of age-related dementia. At least 15 mutations in the human gene PRESENILIN 2 (PSEN2) have been found to cause familial Alzheimer’s disease (fAD). Zebrafish possess an orthologous gene, psen2, and present opportunities for investigation of PRESENILIN function related to Alzheimer’s disease. The most prevalent and best characterized fAD mutation in PSEN2 is N141I. The equivalent codon in zebrafish psen2 is N140. We used genome editing technology in zebrafish to target generation of mutations to the N140 codon. We isolated two mutations: psen2N140fs, causing truncation of the coding sequence, and psen2T141_L142delinsMISLISV, that deletes the two codons immediately downstream of N140 and replaces them with seven codons coding for amino acid residues MISLISV. Thus, like almost every fAD mutation in the PRESENILIN genes, this latter mutation does not truncate the gene’s open reading frame.
2020-09-19 | GSE158233 | GEO
Project description:PSEN1 ΔE9 mutation causes a familial form of Alzheimer's disease. We have previously shown that human induced pluripotent stem cell (iPSC)-derived astrocytes carrying PSEN1 ΔE9 mutation exhibit transcriptional and functional abnormalities (Stem Cell Reports. 2017;9:1885-1897). Here we injected glial progenitors derived from 2 pairs of PSEN1 ΔE9 mutant- isogenic CTRL iPSCs intracerebroventricularly into newborn mice. At the age of 18 months, mouse hippocampi containing human cells (5 x PSEN1 ΔE9 + 6 x CTRL, all from male mice) were quickly dissected out and bulk RNA sequencing analysis was performed. Our results shed more light on the efffect of PSEN1 ΔE9 mutation on human glia in vivo as well as on the effect of the presence of mutant human glia on the surrounding healthy mouse cells.
2022-12-15 | GSE221027 | GEO
Project description:Mutations in presenilin 1 (PSEN1) cause a familiar form of Alzheimer's disease (AD). We have obtained skin biopsies from two individuals carrying PSEN1 exon9 deletion and reprogrammed skin fibroblasts into induced pluripotent stem cells (iPSCs). To get controls, we have corrected PSEN1 exon9 deletion by CRISPR/Cas9 technique. Since astrocytes play role in AD pathogenesis, we further differentiated iPSCs into astrocytes. We ran RNA sequencing analysis to compare our iPSC-derived astrocytes with previously published data on human astrocytes and to identify genes and pathways affected by PSEN1 exon 9 deletion.
2019-12-31 | GSE138695 | GEO
Project description:Zebrafish - modelling familialAlzheimer's disease using heterozygous K97fs mutation in locus psen1
| PRJEB24858 | ENA
Project description:Genome wide DNA methylation profiling of normal and APP/PSEN1 mice. A custom Illumina Golden Gate DNA methylation Beadchip was used to obtain DNA methylation profiles across approximately 800 CpGs. Bisulphite converted DNA from the 96 samples were hybridised to the Illumina custom golden gate DNA methylation array.
2015-12-05 | E-GEOD-42745 | biostudies-arrayexpress
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