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.© 2013.

authors

• Bhaskar, Kiran
• Maphis, Nicole
• Xu, Yuexian
• Varvel, Nicholas H
• Kokiko-Cochran, Olga N
• Weick, Jason P
• Staugaitis, Susan M
• Cardona, Astrid
• Ransohoff, Richard M
• Herrup, Karl
• Lamb, Bruce T

publication date

• January 1, 2014

published in

• Neurobiology of disease  Journal

keywords

• Alzheimer Disease
• Amyloid beta-Peptides
• Animals
• Cell Cycle
• Cells, Cultured
• Frontal Lobe
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Microglia
• Neurons
• Temporal Lobe
• Tumor Necrosis Factor-alpha

Digital Object Identifier (DOI)

• https://doi.org/10.1016/j.nbd.2013.10.007

PubMed ID

• 24141019

start page

• 273

end page

• 285

volume

• 62

number