Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6022028 | Neurobiology of Disease | 2014 | 13 Pages |
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 (AβO)-mediated microglial activation induced neuronal CCEs via the tumor-necrosis factor-α (TNFα) 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 TNFα signaling pathway. Third, genetic deficiency of TNFα in R1.40 mice (R1.40-Tnfαâ/â) 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 TNFα as the responsible cytokine, in promoting neuronal CCEs in the pathogenesis of AD.
Keywords
cox2Tumor necrosis factor-α (TNFα)IDVPCNAIKKα/βTNFRINFγMAP2IL-1βPFASTAT3NOSGFPCCENSAIDTNFαLPSIL-6PBSPI3KJnkROIc-Jun Kinasep38 MAPKProliferating Cell Nuclear AntigenNeuroinflammationAdoptive transferinterferon-γinterleukin-6Interleukin-1βBrdUbromodeoxyuridineAlzheimer's diseaseTerminal deoxynucleotidyl transferase dUTP nick end labelingtumor necrosis factor-αTUNELRoom temperatureAβoconditioned mediaCyclooxygenase-2Non-steroidal anti-inflammatory drugPhosphate buffered salinePhosphatidylinositol 3-kinaselipopolysaccharidesignal transducer and activator of transcription 3region of interestMicrogliaPASnitric oxide synthaseparaformaldehydegreen fluorescent proteinmicrotubule associated protein-2p38 mitogen activated protein kinaseTNF receptor
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Authors
Kiran Bhaskar, Nicole Maphis, Guixiang Xu, Nicholas H. Varvel, Olga N. Kokiko-Cochran, Jason P. Weick, Susan M. Staugaitis, Astrid Cardona, Richard M. Ransohoff, Karl Herrup, Bruce T. Lamb,