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

Pia Jensen, Christa Løth Myhre, Pernille Lassen, Athanasios Metaxas, Asif Manzoor Khan, Kate Lykke Lambertsen, Alicia Babcock, Bente Finsen, Martin Røssel Larsen, Stefan Kempf

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Resumé

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 phosphoproteomics 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 neuroprotective MAPKCREB signaling. Stimulation of human neurons with TNFα 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 TNFα stimulation led to a reduced number of protein/phospho-protein hits compared to siRNA-mediated knockdown of CREB or TNFα stimulation alone and countermeasured the reduced CREB signaling. In vivo data of TNFα knockout mice showed that learning ability did not depend on TNFα per se but that TNFα 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 TNFα in neurons resemble those seen in Alzheimer's disease pathology.

OriginalsprogEngelsk
TidsskriftOncoTarget
Vol/bind8
Udgave nummer36
Sider (fra-til)60223-60242
ISSN1949-2553
DOI
StatusUdgivet - 2017

Fingeraftryk

Neurons
Alzheimer Disease
Small Interfering RNA
Proteins
Pathology
In Vitro Techniques

Citer dette

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title = "TNFα 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 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 phosphoproteomics 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 neuroprotective MAPKCREB signaling. Stimulation of human neurons with TNFα 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 TNFα stimulation led to a reduced number of protein/phospho-protein hits compared to siRNA-mediated knockdown of CREB or TNFα stimulation alone and countermeasured the reduced CREB signaling. In vivo data of TNFα knockout mice showed that learning ability did not depend on TNFα per se but that TNFα 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 TNFα in neurons resemble those seen in Alzheimer's disease pathology.",
keywords = "Alzheimer's disease, LPS, MTOR, Neuroinflammation, Post translational modification",
author = "Pia Jensen and Myhre, {Christa L{\o}th} and Pernille Lassen and Athanasios Metaxas and Khan, {Asif Manzoor} and Lambertsen, {Kate Lykke} and Alicia Babcock and Bente Finsen and Larsen, {Martin R{\o}ssel} and Stefan Kempf",
year = "2017",
doi = "10.18632/oncotarget.19428",
language = "English",
volume = "8",
pages = "60223--60242",
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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; Myhre, Christa Løth; Lassen, Pernille; Metaxas, Athanasios; Khan, Asif Manzoor; Lambertsen, Kate Lykke; Babcock, Alicia; Finsen, Bente; Larsen, Martin Røssel; Kempf, Stefan.

I: OncoTarget, Bind 8, Nr. 36, 2017, s. 60223-60242.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - TNFα affects CREB-mediated neuroprotective signaling pathways of synaptic plasticity in neurons as revealed by proteomics and phospho-proteomics

AU - Jensen, Pia

AU - Myhre, Christa Løth

AU - Lassen, Pernille

AU - Metaxas, Athanasios

AU - Khan, Asif Manzoor

AU - Lambertsen, Kate Lykke

AU - Babcock, Alicia

AU - Finsen, Bente

AU - Larsen, Martin Røssel

AU - Kempf, Stefan

PY - 2017

Y1 - 2017

N2 - 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 phosphoproteomics 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 neuroprotective MAPKCREB signaling. Stimulation of human neurons with TNFα 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 TNFα stimulation led to a reduced number of protein/phospho-protein hits compared to siRNA-mediated knockdown of CREB or TNFα stimulation alone and countermeasured the reduced CREB signaling. In vivo data of TNFα knockout mice showed that learning ability did not depend on TNFα per se but that TNFα 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 TNFα in neurons resemble those seen in Alzheimer's disease pathology.

AB - 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 phosphoproteomics 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 neuroprotective MAPKCREB signaling. Stimulation of human neurons with TNFα 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 TNFα stimulation led to a reduced number of protein/phospho-protein hits compared to siRNA-mediated knockdown of CREB or TNFα stimulation alone and countermeasured the reduced CREB signaling. In vivo data of TNFα knockout mice showed that learning ability did not depend on TNFα per se but that TNFα 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 TNFα in neurons resemble those seen in Alzheimer's disease pathology.

KW - Alzheimer's disease

KW - LPS

KW - MTOR

KW - Neuroinflammation

KW - Post translational modification

U2 - 10.18632/oncotarget.19428

DO - 10.18632/oncotarget.19428

M3 - Journal article

C2 - 28753583

VL - 8

SP - 60223

EP - 60242

JO - OncoTarget

JF - OncoTarget

SN - 1949-2553

IS - 36

ER -