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, Bruce T. Lamb

Research output: Contribution to journalArticle

77 Scopus citations

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-Ju. n 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.

Original languageEnglish (US)
Pages (from-to)273-285
Number of pages13
JournalNeurobiology of Disease
Volume62
DOIs
StatePublished - Feb 2014
Externally publishedYes

Keywords

  • Adoptive transfer
  • Alzheimer's disease
  • C-Jun Kinase (JNK)
  • Microglia
  • Neuroinflammation
  • Neuronal cell cycle
  • Tumor necrosis factor-α (TNFα)

ASJC Scopus subject areas

  • Neurology

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  • Cite this

    Bhaskar, K., Maphis, N., Xu, G., Varvel, N. H., Kokiko-Cochran, O. N., Weick, J. P., Staugaitis, S. M., Cardona, A., Ransohoff, R. M., Herrup, K., & Lamb, B. T. (2014). Microglial derived tumor necrosis factor-α drives Alzheimer's disease-related neuronal cell cycle events. Neurobiology of Disease, 62, 273-285. https://doi.org/10.1016/j.nbd.2013.10.007