Novel roles of TNF death receptor in amyloidosis in vivo

描述(申请人提供)：肿瘤坏死因子I型受体(TNFRI)是一种死亡受体，介导细胞凋亡，在神经系统和免疫系统之间的相互作用中发挥关键作用。在患有神经退行性疾病的大脑中，死亡受体激活和信号级联介导的神经元死亡之间的直接联系仍然没有定论。我们最近证实，淀粉样β蛋白(Abeta)是阿尔茨海默病(AD)脑内斑块的主要成分，它诱导神经细胞凋亡，这是通过改变凋亡蛋白激活因子(APAF-1)的表达，进而诱导核因子-KB的激活来实现的。与野生型(WT)小鼠相比，Abeta诱导的神经细胞凋亡减少，Apaf-1表达降低，且未见核因子-KB的激活，提示在Abeta诱导的神经元死亡中，肿瘤坏死因子死亡受体级联是必需的。为了扩大和进一步研究其体内机制，我们提出，通过基因抑制APP小鼠的肿瘤坏死因子死亡受体，可能会减少AD样病理，最终防止神经元丢失。

DESCRIPTION (provided by applicant): 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. We have recently demonstrated that amyloid-beta protein (Abeta) a major component of plaques in the Alzheimer's diseased (AD) brain, induces neuronal apoptosis and this was mediated via alteration of apoptotic protease-activating factor (Apaf-1) expression that in turn induced activation of NF-KB. Abeta-induced neuronal apoptosis was reduced with lower Apaf-1 expression and little NF-KB activation was found in the neurons with mutated Apaf-1 or a deletion of TNFRI compared to the cells from wild type (WT) mice, suggesting that the TNF death receptor cascade is required for Abeta induced neuron death in vitro. To expand and further study the mechanisms in vivo, we propose that genetic inhibition of the TNF death receptor in APP mice may reduce AD-like pathology and ultimately prevent neuronal loss.