PMID- 24141019 OWN - NLM STAT- MEDLINE DCOM- 20140903 LR - 20211021 IS - 1095-953X (Electronic) IS - 0969-9961 (Print) IS - 0969-9961 (Linking) VI - 62 DP - 2014 Feb TI - Microglial derived tumor necrosis factor-alpha drives Alzheimer's disease-related neuronal cell cycle events. PG - 273-85 LID - S0969-9961(13)00282-9 [pii] LID - 10.1016/j.nbd.2013.10.007 [doi] AB - 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 (AbetaO)-mediated microglial activation induced neuronal CCEs via the tumor-necrosis factor-alpha (TNFalpha) 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 TNFalpha signaling pathway. Third, genetic deficiency of TNFalpha in R1.40 mice (R1.40-Tnfalpha(-/-)) 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 TNFalpha as the responsible cytokine, in promoting neuronal CCEs in the pathogenesis of AD. CI - (c) 2013. FAU - Bhaskar, Kiran AU - Bhaskar K AD - Department of Molecular Genetics and Microbiology, University of New Mexico, MSC08 4660, 1 University of New Mexico, Albuquerque, NM 87131, USA. Electronic address: kbhaskar@salud.unm.edu. FAU - Maphis, Nicole AU - Maphis N AD - Department of Molecular Genetics and Microbiology, University of New Mexico, MSC08 4660, 1 University of New Mexico, Albuquerque, NM 87131, USA. Electronic address: NMaphis@salud.unm.edu. FAU - Xu, Guixiang AU - Xu G AD - Department of Neurosciences, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: xug@ccf.org. FAU - Varvel, Nicholas H AU - Varvel NH AD - Department of Cellular Neurology, University of Tubingen, Hertie Institute for Clinical Brain Research, Otfried-Muller-Strasse 27, 72076 Tubingen, Germany. Electronic address: nicholas.varval@gmail.com. FAU - Kokiko-Cochran, Olga N AU - Kokiko-Cochran ON AD - Department of Neurosciences, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: kokikoo@ccf.org. FAU - Weick, Jason P AU - Weick JP AD - Department of Neurosciences, University of New Mexico, MSC08 4740, 1 University of New Mexico, Albuquerque, NM 87131, USA. Electronic address: JPWeick@salud.unm.edu. FAU - Staugaitis, Susan M AU - Staugaitis SM AD - Department of Neurosciences, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: staugas@ccf.org. FAU - Cardona, Astrid AU - Cardona A AD - Department of Biology, University of Texas San Antonio, West Campus/Tobin lab MBT 1.216, San Antonio, TX 78249, USA. Electronic address: Astrid.Cardona@utsa.edu. FAU - Ransohoff, Richard M AU - Ransohoff RM AD - Department of Neurosciences, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: ransohr@ccf.org. FAU - Herrup, Karl AU - Herrup K AD - Department of Cell Biology and Neuroscience, Rutgers University, Nelson Hall, Busch Campus, Piscataway, NJ 08855, USA. Electronic address: Herrup@dls.rutgers.edu. FAU - Lamb, Bruce T AU - Lamb BT AD - Department of Neurosciences, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: lambb@ccf.org. LA - eng GR - R01 NS074804/NS/NINDS NIH HHS/United States GR - AG023012/AG/NIA NIH HHS/United States GR - R01 NS071022/NS/NINDS NIH HHS/United States GR - 5R21NS077089-03/NS/NINDS NIH HHS/United States GR - GM095426-02/GM/NIGMS NIH HHS/United States GR - R21 NS077089/NS/NINDS NIH HHS/United States GR - NS071022-03/NS/NINDS NIH HHS/United States GR - SC1 GM095426/GM/NIGMS NIH HHS/United States GR - NS074804/NS/NINDS NIH HHS/United States GR - R01 AG023012/AG/NIA NIH HHS/United States GR - R21 AG046399/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20131017 PL - United States TA - Neurobiol Dis JT - Neurobiology of disease JID - 9500169 RN - 0 (Amyloid beta-Peptides) RN - 0 (Tumor Necrosis Factor-alpha) SB - IM MH - Alzheimer Disease/*metabolism MH - Amyloid beta-Peptides/pharmacology MH - Animals MH - *Cell Cycle MH - Cells, Cultured MH - Frontal Lobe/metabolism MH - Humans MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Microglia/drug effects/*metabolism MH - Neurons/*metabolism MH - Temporal Lobe/metabolism MH - Tumor Necrosis Factor-alpha/*metabolism PMC - PMC3877710 MID - NIHMS532580 OTO - NOTNLM OT - AD OT - Adoptive transfer OT - Alzheimer's disease OT - AbetaF OT - AbetaO OT - BrdU OT - Bromodeoxyuridine OT - CCE OT - CM OT - COX2 OT - GFP OT - IDV OT - IKKalpha/beta OT - IL-1beta OT - IL-6 OT - INFgamma OT - IkappaB kinase alpha/beta OT - JNK OT - LPS OT - MAP2 OT - Microglia OT - NOS OT - NSAID OT - Neuroinflammation OT - Neuronal cell cycle OT - PAS OT - PBS OT - PCNA OT - PFA OT - PI3K OT - Phosphatidylinositol 3-kinase OT - ROI OT - RT OT - STAT3 OT - Signal transducer and activator of transcription 3 OT - TNF receptor OT - TNFR OT - TNFalpha OT - TUNEL OT - Terminal deoxynucleotidyl transferase dUTP nick end labeling OT - Tumor Necrosis Factor-alpha OT - Tumor necrosis factor-alpha (TNFalpha) OT - c-Jun Kinase OT - c-Jun Kinase (JNK) OT - cell cycle events OT - conditioned media OT - cyclooxygenase-2 OT - fibrillar amyloid-beta peptide OT - green fluorescent protein OT - integrated density value OT - interferon-gamma OT - interleukin-1beta OT - interleukin-6 OT - lipopolysaccharide OT - microtubule associated protein-2 OT - nitric oxide synthase OT - non-steroidal anti-inflammatory drug OT - oligomeric amyloid-beta peptide OT - p38 MAPK OT - p38 mitogen activated protein kinase OT - paraformaldehyde OT - phosphate buffered saline OT - proliferating cell nuclear antigen OT - protein-A-sepharose OT - region of interest OT - room temperature EDAT- 2013/10/22 06:00 MHDA- 2014/09/04 06:00 PMCR- 2015/02/01 CRDT- 2013/10/22 06:00 PHST- 2013/06/29 00:00 [received] PHST- 2013/10/01 00:00 [revised] PHST- 2013/10/06 00:00 [accepted] PHST- 2013/10/22 06:00 [entrez] PHST- 2013/10/22 06:00 [pubmed] PHST- 2014/09/04 06:00 [medline] PHST- 2015/02/01 00:00 [pmc-release] AID - S0969-9961(13)00282-9 [pii] AID - 10.1016/j.nbd.2013.10.007 [doi] PST - ppublish SO - Neurobiol Dis. 2014 Feb;62:273-85. doi: 10.1016/j.nbd.2013.10.007. Epub 2013 Oct 17.