Unknown,Transcriptomics,Genomics,Proteomics

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RNA-Seq of human fibroblasts, induced neurons (iNs), iPSCs, and iPSC-derived neurons, and ATAC-Seq of fibroblasts and iNs from a cohort of Alzheimer patients and controls

ABSTRACT: We have obtained fibroblast cultures from old adult human donors, including Alzheimer patients. The fibroblasts were reprogrammed into directly induced neurons (iNs) to serve as an adult-like and age-equivalent model for aging and neurodegeneration. We also generated iPSCs and rejuvenated iPSC-derived induced neurons from a subset of the same cohort as controls. The cells were analyzed using several assays, including mRNA-Seq, ATAC-Seq and DNA methylation EPIC array analysis.

INSTRUMENT(S): Illumina HiSeq 2500

ORGANISM(S): Homo sapiens

SUBMITTER: Jerome Mertens

PROVIDER: E-MTAB-10352 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Neuroinflammation is a hallmark of various neurological diseases such as Alzheimer’s disease. The aim of the study was to elucidate the dose-dependent in vitro molecular mechanism of TNFα in neurons related to neuroprotection and -degeneration. We performed a quantitative proteomics and phospho-proteomics study in HT22 neuronal cells as well as differentiated human neurons to elucidate alterations in TNFα dose-dependent (0.1 – 100.0 ng/ml) signaling pathways. We report here that 10.0 ng/ml TNFα reduces mitochondrial signaling and inhibits protein translation signaling related to mTOR but leads also at the same time to induction of neuroprotective MAPK-CREB signaling after 24 hours in HT22 cells. Stimulation of TNFα (1.0 ng/ml, 24 hours) in human neurons reveals similar cellular mechanisms on protein translation signaling related to mTOR as seen in HT22 cells at 10.0 ng/ml dose whereas mitochondrial membrane potential and reactive oxygen species level were not changed. SiRNA-mediated knockdown of CREB in human neurons prior to TNFα stimulation led to a reduced number of protein/phospho-protein hits compared to siRNA-mediated knockdown of CREB or TNFα stimulation alone and countermeasures the reduced CREB signaling. In vivo data of TNFα knock-out transgenic mice showed that learning ability does not depend on TNFα during normal aging but that TNFα preserves the learning and memory ability during episodes of systemic inflammation resembling the persistent neuroinflammation status as seen in Alzheimer´s disease. This may be based on modulation of CREB as revealed by our in vitro studies. Our data indicate that several molecular targets and signaling pathways induced by TNFα in neurons resemble those of Alzheimer´s pathology. It may suggest that TNFα functions as a contributing factor to this neurodegenerative disease but has also at the same time neuroprotective properties regulating learning and memory formation under neuroinflammatory status.

Dataset Information

RNA-Seq of human fibroblasts, induced neurons (iNs), iPSCs, and iPSC-derived neurons, and ATAC-Seq of fibroblasts and iNs from a cohort of Alzheimer patients and controls

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