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Elucidation of the inflammatory and neuroprotective molecular network of TNFalpha in neurons related to Alzheimer´s disease

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

SUBMITTER: Stefan J. Kempf

LAB HEAD: Martin R. Larsen

PROVIDER: PXD005675 | Pride | 2017-08-08

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	CREBsiRNAnonmodified1new.msf	Msf
	CREBsiRNAnonmodified3new.msf	Msf
	CREBsiRNAphospho1new.msf	Msf
	CREBsiRNAphospho3new.msf	Msf
	HT22TNFaNon-modifiedrep.1.msf	Msf

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Publications

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

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 neuroprotec ...[more]

PMID: 28753583

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