title: Microglial derived tumor necrosis factor-α 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 (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-Tnfα(-/-)) 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.
authors.affiliation: 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.
authors.forename: Kiran
authors.initials: K
authors.lastname: Bhaskar
authors.affiliation: 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.
authors.forename: Nicole
authors.initials: N
authors.lastname: Maphis
authors.affiliation: Department of Neurosciences, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: xug@ccf.org.
authors.forename: Guixiang
authors.initials: G
authors.lastname: Xu
authors.affiliation: Department of Cellular Neurology, University of Tübingen, Hertie Institute for Clinical Brain Research, Otfried-Müller-Straße 27, 72076 Tübingen, Germany. Electronic address: nicholas.varval@gmail.com.
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Varvel
authors.affiliation: Department of Neurosciences, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: kokikoo@ccf.org.
authors.forename: Olga N
authors.initials: ON
authors.lastname: Kokiko-Cochran
authors.affiliation: Department of Neurosciences, University of New Mexico, MSC08 4740, 1 University of New Mexico, Albuquerque, NM 87131, USA. Electronic address: JPWeick@salud.unm.edu.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Weick
authors.affiliation: Department of Neurosciences, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: staugas@ccf.org.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Staugaitis
authors.affiliation: 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.
authors.forename: Astrid
authors.initials: A
authors.lastname: Cardona
authors.affiliation: Department of Neurosciences, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: ransohr@ccf.org.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ransohoff
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Nelson Hall, Busch Campus, Piscataway, NJ 08855, USA. Electronic address: Herrup@dls.rutgers.edu.
authors.forename: Karl
authors.initials: K
authors.lastname: Herrup
authors.affiliation: Department of Neurosciences, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: lambb@ccf.org.
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Lamb
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D002453:Cell Cycle; D002478:Cells, Cultured; D005625:Frontal Lobe / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D013702:Temporal Lobe / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D014409:Tumor Necrosis Factor-alpha
keywords: AD; Adoptive transfer; Alzheimer's disease; AβF; AβO; BrdU; Bromodeoxyuridine; CCE; CM; COX2; GFP; IDV; IKKα/β; IL-1β; IL-6; INFγ; IκB kinase α/β; JNK; LPS; MAP2; Microglia; NOS; NSAID; Neuroinflammation; Neuronal cell cycle; PAS; PBS; PCNA; PFA; PI3K; Phosphatidylinositol 3-kinase; ROI; RT; STAT3; Signal transducer and activator of transcription 3; TNF receptor; TNFR; TNFα; TUNEL; Terminal deoxynucleotidyl transferase dUTP nick end labeling; Tumor Necrosis Factor-α; Tumor necrosis factor-α (TNFα); c-Jun Kinase; c-Jun Kinase (JNK); cell cycle events; conditioned media; cyclooxygenase-2; fibrillar amyloid-beta peptide; green fluorescent protein; integrated density value; interferon-γ; interleukin-1β; interleukin-6; lipopolysaccharide; microtubule associated protein-2; nitric oxide synthase; non-steroidal anti-inflammatory drug; oligomeric amyloid-beta peptide; p38 MAPK; p38 mitogen activated protein kinase; paraformaldehyde; phosphate buffered saline; proliferating cell nuclear antigen; protein-A-sepharose; region of interest; room temperature