Mutations in PSEN1 predispose inflammation in an astrocyte model of familial Alzheimer’s disease through disrupted regulated intramembrane proteolysis
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ABSTRACT:
PROVIDER: PRJNA1269544 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR33750702_1.fastq.gz | Fastqsanger.gz | |||
| SRR33750702_2.fastq.gz | Fastqsanger.gz | |||
| SRR33750704_1.fastq.gz | Fastqsanger.gz | |||
| SRR33750704_2.fastq.gz | Fastqsanger.gz |
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Project description:Mutations in PSEN1 cause familial Alzheimer’s disease with almost complete penetrance. Age at onset is highly variable between different PSEN1 mutations and even within families with the same mutation. Current research into late onset Alzheimer’s disease implicates inflammation in both disease onset and progression. PSEN1 is the catalytic subunit of gamma-secretase, responsible for regulated intramembrane proteolysis of numerous substrates that include cytokine receptors. For this reason, we tested the hypothesis that mutations in PSEN1 impact inflammatory responses in astrocytes, thereby contributing to disease progression. We developed patient-derived models of iPSC-astrocytes, representing three lines harbouring PSEN1 mutations and six control lines (including two isogenic controls). Transcriptomic and biochemical assays were used to investigate differential inflammatory responses to TNFa, IL1a and C1q. We show that PSEN1 is upregulated in response to inflammatory stimuli, and this upregulation is disrupted by pathological PSEN1 mutations. Using transcriptomic analyses, we demonstrate that PSEN1 mutant astrocytes have an augmented inflammatory profile in their basal state, concomitant with gene expression signatures revealing dysregulated intramembrane proteolysis and JAK-STAT signalling. Detailed investigation of the JAK-STAT2 signalling pathway showed reduced cell surface expression of IFNAR2, lower STAT2 phosphorylation cascades and delayed NFκB nuclear localisation in PSEN1 mutant astrocytes in response to inflammatory stimuli, thereby implicating the notion of altered cytokine signalling cascades. Finally, we use small molecule modulators of gamma-secretase to confirm a role for PSEN1/gamma-secretase in regulating the astrocytic response to inflammatory stimuli. Together, these data suggest that mutations in PSEN1 enhance cytokine signalling via impaired regulated intramembrane proteolysis, thereby predisposing astrocytic inflammatory profiles. These findings support a two-hit contribution of PSEN1 mutations to fAD pathogenesis, not only impacting APP and Abeta processing but also altering the cellular response to inflammation.
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Project description:Early-onset familial Alzheimer’s disease (EOfAD) is promoted by dominant mutations, enabling the study of Alzheimer’s disease (AD) pathogenic mechanisms through generation of EOfAD-like mutations in animal models. In a previous study, we generated an EOfAD-like mutation, psen1Q96_K97del, in zebrafish and performed a transcriptome analysis comparing entire brains from 6-month-old wild type and heterozygous mutant fish. We identified predicted effects on mitochondrial function and endolysosomal acidification. Here we aimed to determine whether similar effects occur in 7 day post fertilization (dpf) zebrafish larvae that might be exploited in screening of chemical libraries to find ameliorative drugs. We generated clutches of wild type and heterozygous psen1Q96_K97del 7 dpf larvae using a paired-mating strategy to reduce extraneous genetic variation before performing a comparative transcriptome analysis. We identified 228 differentially expressed genes and performed Goseq analysis and gene set enrichment analysis (GSEA). This predicted a significant effect on oxidative phosphorylation, consistent with our earlier observations of predicted effects on ATP synthesis in adult heterozygous psen1Q96_K97del brains. The dysregulation of minichromosome maintenance protein complex (MCM) genes strongly contributed to predicted effects on DNA replication and the cell cycle and may explain earlier observations of genome instability due to PSEN1 mutation. The upregulation of crystallin gene expression may be a response to defective activity of mutant Psen1 protein in endolysosomal acidification. Extracellular matrix (ECM) related genes were downregulated, consistent with previous studies of EOfAD mutant iPSC neurons and postmortem late onset AD brains. Also, changes in expression of genes controlling iron ion transport were observed without identifiable changes in the prevalence of transcripts containing iron responsive elements (IREs) in their 3’ untranslated regions. These changes may, therefore, predispose to the apparent iron dyshomeostasis previously observed in 6-month-old heterozygous psen1Q96_K97del EOfAD-like mutant brains.
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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.
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