• Neurobiology of disease · Feb 2014

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

    • 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, and Bruce T Lamb.
    • 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.
    • Neurobiol. Dis. 2014 Feb 1; 62: 273-85.

    AbstractMassive 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.© 2013.

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