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The transcriptomic landscape of glutamatergic cortical neurons carrying Alzheimer’s disease PSEN1 mutations reveals alterations in structural components, signalling, and ncRNA regulation

ABSTRACT: To investigate gene expression changes related to two fAD mutations (A79V and L150P) in the Presenilin-1 gene (PSEN1) we compared the transcriptomes (polyA and total) of glutamatergic cortical neurons derived from fAD-mutant human induced pluripotent stem cells and their individual isogenic controls generated via precision CRISPR/Cas9 genome editing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE211993 | GEO | 2023/01/24

REPOSITORIES: GEO

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Gene expression profile of sporadic and PSEN1 early-onset Alzheimer’s Disease

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.

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Gene expression profile of sporadic and PSEN1 early-onset Alzheimer’s Disease

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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 A42 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 A42 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.

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The transcriptomic landscape of glutamatergic cortical neurons carrying Alzheimer’s disease PSEN1 mutations reveals alterations in structural components, signalling, and ncRNA regulation

Project description: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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β2-adrenergic agonists rescue lysosome acidification and function in PSEN1 deficiency by reversing defective ER to lysosome delivery of ClC-7

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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.

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Project description:Zebrafish - modelling familialAlzheimer's disease using heterozygous K97fs mutation in locus psen1

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