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

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 amyloidbeta peptide (A beta O)-mediated microglial activation induced neuronal CCEs via the tumor-necrosis factor-a (TNF alpha) 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 TNFa signaling pathway. Third, genetic deficiency of TNFa in R1.40 mice (R1.40-Tnf alpha(-/-)) 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 TNFa as the responsible cytokine, in promoting neuronal CCEs in the pathogenesis of AD. (C) 2013 Elsevier Inc. All rights reserved.