中文摘要：

阿尔茨海默病（Alzheimer′s disease,AD）是一种神经系统退行性疾病,近年来许多研究发现AD与细胞凋亡关系密切,有研究证明肿瘤坏死因子（tumor necrosis factor-α,TNF-α）的合成过量会造成神经细胞的凋亡从而导致AD等神经退行性疾病的发生,然而人们对TNF-α造成神经细胞凋亡的分子机制并不了解.采用激光共聚焦扫描成像技术和荧光共振能量转移（fluorescence resonance energy transfer,FRET）技术在活细胞中实时对TNF-α诱导分化PC12细胞凋亡的信号通路进行了细致的研究.实验结果证明,TNF-α诱导的分化PC12细胞凋亡会经过线粒体和非线粒体途径,并通过激活核转录因子（NF-κB）上调Bcl-xL的表达来抑制经过线粒体的凋亡途径.进一步的研究证明,BimL会在线粒体上替换原来被Bcl-xL抑制的Bax,从而让Bax寡聚化,进而引发细胞凋亡,而c-Jun氨基末端激酶（JNK）抑制剂SP600125可以抑制Bax寡聚化.此外,在未分化PC12细胞中共表达GFP-BimL和YFP-Bax质粒,发现BimL可以促进Bax发生聚集,并且它们二者之间不是直接发生相互作用.上述结果证明,BimL在TNF-α诱导神经细胞凋亡过程中起到了重要作用,BimL在TNF-α诱导分化PC12细胞凋亡的过程中间接激活了Bax.

英文摘要：

Alzheimer＇s disease （AD） is a neurodegenerative disease. Recent years, AD has been found closely related to cell apoptosis. It is reported that the synthesis of excessive tumor necrosis factor-α （TNF-α） has been widely considered as a potential inducer of apoptosis contributing to neurodegenerative disease such as AD. However, the molecular mechanism of TNF-α-mediated apoptosis in neuron remains unclear. The signaling pathways involved in TNF-α-induced apoptosis in living differentiated PC12 cells were investigated by using confocal microscope and FRET （fluorescence resonance energy transfer） technique for the first time. Experimental results show that the TNF-α induced apoptosis in differentiated PC12 cells through ＂extrinsic＂ or death receptor-initiated pathway, and the ＂intrinsic＂ or mitochondrial pathway. NF-κB can inhibit mitochondrial pathway apoptosis through up-regulation of Bcl-xL by TNF-α induced. Further results show that BimL displaces Bcl-xLin the mitochondria and promotes Bax translocation during TNF-α-induced apoptosis. Furthermore, SP600125 （specific inhibitor of JNK） can inhibit the Bax translocation to mitochondria. Finally, Bax is found to translocate to mitochondria in Nave PC12 cells with co-expressing of GFP-BimL and YFP-Bax. The research demonstrates the important role of BimL, and reveals that BimL activate Bax indirectly during TNF-α-induced apoptosis.