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Microglial derived tumor necrosis factor-? drives Alzheimer's disease-related neuronal cell cycle events.

ABSTRACT: Massive neuronal loss is a key pathological hallmark of Alzheimer's disease (AD). However, the mechanisms are still unclear. Here we demonstrate that neuroinflammation, cell autonomous to microglia, is capable of inducing neuronal cell cycle events (CCEs), which are toxic for terminally differentiated neurons. First, oligomeric amyloid-beta peptide (A?O)-mediated microglial activation induced neuronal CCEs via the tumor-necrosis factor-? (TNF?) and the c-Jun Kinase (JNK) signaling pathway. Second, adoptive transfer of CD11b+ microglia from AD transgenic mice (R1.40) induced neuronal cyclin D1 expression via TNF? signaling pathway. Third, genetic deficiency of TNF? in R1.40 mice (R1.40-Tnf?(-/-)) failed to induce neuronal CCEs. Finally, the mitotically active neurons spatially co-exist with F4/80+ activated microglia in the human AD brain and that a portion of these neurons are apoptotic. Together our data suggest a cell-autonomous role of microglia, and identify TNF? as the responsible cytokine, in promoting neuronal CCEs in the pathogenesis of AD.

SUBMITTER: Bhaskar K

PROVIDER: S-EPMC3877710 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Microglial derived tumor necrosis factor-α drives Alzheimer's disease-related neuronal cell cycle events.

Bhaskar Kiran K Maphis Nicole N Xu Guixiang G Varvel Nicholas H NH Kokiko-Cochran Olga N ON Weick Jason P JP Staugaitis Susan M SM Cardona Astrid A Ransohoff Richard M RM Herrup Karl K Lamb Bruce T BT

Neurobiology of disease 20131017

Massive neuronal loss is a key pathological hallmark of Alzheimer's disease (AD). However, the mechanisms are still unclear. Here we demonstrate that neuroinflammation, cell autonomous to microglia, is capable of inducing neuronal cell cycle events (CCEs), which are toxic for terminally differentiated neurons. First, oligomeric amyloid-beta peptide (AβO)-mediated microglial activation induced neuronal CCEs via the tumor-necrosis factor-α (TNFα) and the c-Jun Kinase (JNK) signaling pathway. Secon ...[more]

PMID: 24141019

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Project description:This study aims to investigate the prevalence of short-term and long-term adverse events associated with tumor necrosis factor-α (TNF-α) blocker treatment in Chinese Han patients suffering from ankylosing spondylitis (AS).The study included 402 Chinese Han AS patients treated with TNF-α blockers. Baseline data was collected. All patients were monitored for adverse events 2 hours following administration. Long-term treatment was evaluated at 8, 12, 52 and 104 weeks follow-up for 172 patients treated with TNF-α blockers.Short-term adverse events occurred in 20.15% (81/402), including rash (3.5%; 14/402), pruritus (1.2%; 5/402), nausea (2.2%; 9/402), headache (0.7%; 3/402), skin allergies (4.0%; 16/402), fever (0.5%; 2/402), palpitations (3.0%; 12/402), dyspnea (0.5%; 2/402), chest pain (0.2%; 1/402), [corrected] abdominal pain (1.0%; 4/402), hypertension (2.2%; 9/402), papilledema (0.5%; 2/402), laryngeal edema (0.2%; 1/402) and premature ventricular contraction (0.2%; 1/402). Long-term adverse events occurred in 59 (34.3%; 59/172) patients, including pneumonia (7.6%; 13/172), urinary tract infections (9.9%; 17/172), otitis media (4.7%; 8/172), tuberculosis are (3.5%; 6/172) [corrected], abscess (1.2%; 2/172), oral candidiasis (0.6%; 1/172), elevation of transaminase (1.7%; 3/172), anemia (1.2%; 2/172), hematuresis (0.6%; 1/172), constipation (2.3%; 4/172), weight loss (0.6%; 1/172), exfoliative dermatitis (0.6%; 1/172). CRP, ESR and disease duration were found to be associated with an increased risk of immediate and long-term adverse events (P<0.05). Long-term treatment with Infliximab was associated with more adverse events than rhTNFR-Fc (P<0.01).This study reports on the prevalence of adverse events in short-term and long-term treatment with TNF-α blocker monotherapy in Chinese Han AS patients. Duration of disease, erythrocyte sedimentation rate, and c-reactive protein serum levels were found to be associated with increased adverse events with anti-TNF-α therapy. Long-term treatment with Infliximab was associated with more adverse events than rhTNFR-Fc.

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Project description:Post-ischemic microglial activation may contribute to neuronal damage through the release of large amounts of pro-inflammatory cytokines and neurotoxic factors. The involvement of microRNAs (miRNAs) in the pathogenesis of disorders related to the brain and central nervous system has been previously studied, but it remains unknown whether the production of pro-inflammatory cytokines is regulated by miRNAs.BV-2 and primary rat microglial cells were activated by exposure to oxygen-glucose deprivation (OGD). Global cerebral ischemia was induced using the four-vessel occlusion (4-VO) model in rats. Induction of pro-inflammatory and neurotoxic factors, such as tumor necrosis factor (TNF)-?, interleukin (IL)-1?, and nitric oxide (NO), were assessed by ELISA, immunofluorescence, and the Griess assay, respectively. The miRNA expression profiles of OGD-activated BV-2 cells were subsequently compared with the profiles of resting cells in a miRNA microarray. BV-2 and primary rat microglial cells were transfected with miR-181c to evaluate its effects on TNF-? production after OGD. In addition, a luciferase reporter assay was conducted to confirm whether TNF-? is a direct target of miR-181c.OGD induced BV-2 microglial activation in vitro, as indicated by the overproduction of TNF-?, IL-1?, and NO. Global cerebral ischemia/reperfusion injury induced microglial activation and the release of pro-inflammatory cytokines in the hippocampus. OGD also downregulated miR-181c expression and upregulated TNF-? expression. Overproduction of TNF-? after OGD-induced microglial activation provoked neuronal apoptosis, whereas the ectopic expression of miR-181c partially protected neurons from cell death caused by OGD-activated microglia. RNAinterference-mediated knockdown of TNF-? phenocopied the effect of miR-181c-mediated neuronal protection, whereas overexpression of TNF-? blocked the miR-181c-dependent suppression of apoptosis. Further studies showed that miR-181c could directly target the 3'-untranslated region of TNF-? mRNA, suppressing its mRNA and protein expression.Our data suggest a potential role for miR-181c in the regulation of TNF-? expression after ischemia/hypoxia and microglia-mediated neuronal injury.

Dataset Information

Microglial derived tumor necrosis factor-? drives Alzheimer's disease-related neuronal cell cycle events.

Publications

Microglial derived tumor necrosis factor-α drives Alzheimer's disease-related neuronal cell cycle events.

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