Li Rena, Yang Libang, Lindholm Kristina, Konishi Yoshihiro, Yue Xu, Hampel Harald, Zhang Dai, Shen Yong
Haldeman Laboratory of Molecular and Cellular Neurobiology, Sun Health Research Institute, Sun City, Arizona 85351, USA.
J Neurosci. 2004 Feb 18;24(7):1760-71. doi: 10.1523/JNEUROSCI.4580-03.2004.
Tumor necrosis factor type I receptor (TNFRI), a death receptor, mediates apoptosis and plays a crucial role in the interaction between the nervous and immune systems. A direct link between death receptor activation and signal cascade-mediated neuron death in brains with neurodegenerative disorders remains inconclusive. Here, we show that amyloid-beta protein (Abeta), a major component of plaques in the Alzheimer's diseased brain, induces neuronal apoptosis through TNFRI by using primary neurons overexpressing TNFRI by viral infection or neurons from TNFRI knock-out mice. This was mediated via alteration of apoptotic protease-activating factor (Apaf-1) expression that in turn induced activation of nuclear factor kappaB (NF-kappaB). Abeta-induced neuronal apoptosis was reduced with lower Apaf-1 expression, and little NF-kappaB activation was found in the neurons with mutated Apaf-1 or a deletion of TNFRI compared with the cells from wild-type (WT) mice. Our studies suggest a novel neuronal response of Abeta, which occurs through a TNF receptor signaling cascade and a caspase-dependent death pathway.
I型肿瘤坏死因子受体（TNFRI）是一种死亡受体，介导细胞凋亡，在神经和免疫系统的相互作用中起关键作用。在患有神经退行性疾病的大脑中，死亡受体激活与信号级联介导的神经元死亡之间的直接联系仍无定论。在此，我们表明，淀粉样β蛋白（Aβ）是阿尔茨海默病大脑中斑块的主要成分，通过病毒感染过表达TNFRI的原代神经元或TNFRI基因敲除小鼠的神经元，通过TNFRI诱导神经元凋亡。这是通过凋亡蛋白酶激活因子（Apaf-1）表达的改变介导的，进而诱导核因子κB（NF-κB）的激活。较低的Apaf-1表达可减少Aβ诱导的神经元凋亡，与野生型（WT）小鼠的细胞相比，在具有突变Apaf-1或缺失TNFRI的神经元中几乎未发现NF-κB激活。我们的研究表明，Aβ通过TNF受体信号级联和半胱天冬酶依赖性死亡途径产生一种新的神经元反应。
