The Induction of the TNFα Death Domain Signaling Pathway in Alzheimer's Disease Brain
The Induction of the TNFα Death Domain Signaling Pathway in Alzheimer's Disease Brain
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DOI：
10.1023/a:1022337519035
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发表时间：
2003-02
影响因子：
4.4
通讯作者：
Ming Zhao;D. Cribbs;A. Anderson;Brian J Cummings;Joseph H. Su;A. Wasserman;C. Cotman
中科院分区：
文献类型：
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作者：
Ming Zhao;D. Cribbs;A. Anderson;Brian J Cummings;Joseph H. Su;A. Wasserman;C. Cotman
肿瘤坏死因子-α死亡结构域途径在多种条件下导致细胞退变。这项研究调查了这一死亡区域通路是在阿尔茨海默病(AD)进展过程中在大脑中逐渐诱导的假说。AD患者肿瘤坏死因子-α、肿瘤坏死因子受体-1、肿瘤坏死因子受体相关死亡结构域和半胱氨酸天冬氨酸氨基转移酶-3等促凋亡标志物水平升高，分别是年龄匹配对照组的2~10倍和过渡期患者的1~3倍。与之形成鲜明对比的是，潜在的神经保护性肿瘤坏死因子受体2型和Fas相关死亡域样白介素1β转换酶抑制蛋白在AD组与年龄匹配的对照组相比显著降低(P<；.01)。总体而言，阿尔茨海默病患者脑组织中促细胞凋亡的成分增加了5倍，其中肿瘤坏死因子-R1增加了5倍，翻转减少了12倍。这些变化可能转化为退化潜力的增加，因为下游效应因子caspase-3和肿瘤坏死因子途径的产物也随着肿瘤坏死因子促凋亡条件的增强而增加。我们的发现表明，在AD神经元变性的早期阶段，肿瘤坏死因子死亡受体通路和半胱氨酸氨基转移酶被激活。
The tumor necrosis factor-α death domain pathway contributes to cellular degeneration in a variety of conditions. This study investigates the hypothesis that this death domain pathway is progressively induced in the brain during the progression of Alzheimer's disease (AD). AD cases had increased levels of proapoptotic markers including tumor necrosis factor-α (TNFα), TNF receptor type 1 (TNF-R1), TNF receptor–associated death domain (TRADD), and caspase-3, 2- to 10-fold higher (P < .01) than age-matched controls and 1 to 3 times higher than transitional cases. In striking contrast, potentially neuroprotective TNF receptor type 2 (TNF-R2), and Fas-associated death domain-like interleukin-1β–converting enzyme (FLICE) inhibitor protein (FLIP) were decreased in AD as compared with age-matched control cases (P < .01). Overall, there was an elevation in proapoptotic elements, including a 5-fold increase in TNF-R1 and a 12-fold decrease in FLIP in AD brains. These changes may translate to increased degenerative potential because the downstream effector caspase-3 and product of the TNF pathway was also increased in parallel with enhanced TNF proapoptotic conditions. Our findings suggest that the TNF death receptor pathway and caspases are activated in the early stages of neuronal degeneration in AD.