Department of Molecular Genetics and Microbiology, University of New Mexico, MSC08 4660, 1 University of New Mexico, Albuquerque, NM 87131, USA.
Department of Neurosciences, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Neurobiol Dis. 2014 Feb;62:273-85. doi: 10.1016/j.nbd.2013.10.007. Epub 2013 Oct 17.
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.
神经元大量丢失是阿尔茨海默病（AD）的主要病理学特征。然而，其机制仍不清楚。我们在此证明，小胶质细胞自主的神经炎症能够诱导神经元细胞周期事件（CCEs），这对终末分化神经元是有毒的。首先，寡聚淀粉样β肽（AβO）介导的小胶质细胞激活通过肿瘤坏死因子-α（TNFα）和 c-Jun 激酶（JNK）信号通路诱导神经元 CCEs。其次，从 AD 转基因小鼠（R1.40）过继转移 CD11b+小胶质细胞通过 TNFα 信号通路诱导神经元周期蛋白 D1 的表达。第三，R1.40 小鼠中 TNFα 的基因缺失（R1.40-Tnfα(-/-)）未能诱导神经元 CCEs。最后，在人类 AD 大脑中，有丝分裂活性的神经元与 F4/80+活化的小胶质细胞在空间上共存，其中一部分神经元发生凋亡。总之，我们的数据表明小胶质细胞具有自主作用，并确定 TNFα 是促进 AD 发病机制中神经元 CCEs 的负责细胞因子。
