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TNF? affects CREB-mediated neuroprotective signaling pathways of synaptic plasticity in neurons as revealed by proteomics and phospho-proteomics.

ABSTRACT: Neuroinflammation is a hallmark of Alzheimer's disease and TNF? as the main inducer of neuroinflammation has neurodegenerative but also pro-regenerative properties, however, the dose-dependent molecular changes on signaling pathway level are not fully understood. We performed quantitative proteomics and phospho-proteomics to target this point. In HT22 cells, we found that TNF? reduced mitochondrial signaling and inhibited mTOR protein translation signaling but also led to induction of neuroprotective MAPK-CREB signaling. Stimulation of human neurons with TNF? revealed similar cellular mechanisms. Moreover, a number of synaptic plasticity-associated genes were altered in their expression profile including CREB. SiRNA-mediated knockdown of CREB in human neurons prior to TNF? stimulation led to a reduced number of protein/phospho-protein hits compared to siRNA-mediated knockdown of CREB or TNF? stimulation alone and countermeasured the reduced CREB signaling. In vivo data of TNF? knockout mice showed that learning ability did not depend on TNF? per se but that TNF? was essential for preserving the learning ability after episodes of lipopolysaccharide-induced neuroinflammation. This may be based on modulation of CREB/CREB signaling as revealed by the in vitro / in vivo data. Our data show that several molecular targets and signaling pathways induced by TNF? in neurons resemble those seen in Alzheimer's disease pathology.

SUBMITTER: Jensen P

PROVIDER: S-EPMC5601134 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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TNFα affects CREB-mediated neuroprotective signaling pathways of synaptic plasticity in neurons as revealed by proteomics and phospho-proteomics.

Jensen Pia P Myhre Christa L CL Lassen Pernille S PS Metaxas Athanasios A Khan Asif M AM Lambertsen Kate L KL Babcock Alicia A AA Finsen Bente B Larsen Martin R MR Kempf Stefan J SJ

Oncotarget 20170721 36

Neuroinflammation is a hallmark of Alzheimer's disease and TNFα as the main inducer of neuroinflammation has neurodegenerative but also pro-regenerative properties, however, the dose-dependent molecular changes on signaling pathway level are not fully understood. We performed quantitative proteomics and phospho-proteomics to target this point. In HT22 cells, we found that TNFα reduced mitochondrial signaling and inhibited mTOR protein translation signaling but also led to induction of neuroprote ...[more]

PMID: 28947966

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Dataset Information

TNF? affects CREB-mediated neuroprotective signaling pathways of synaptic plasticity in neurons as revealed by proteomics and phospho-proteomics.

Publications

TNFα affects CREB-mediated neuroprotective signaling pathways of synaptic plasticity in neurons as revealed by proteomics and phospho-proteomics.

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