Abeta 17-42 in Alzheimer's disease activates JNK and caspase-8 leading to neuronal apoptosis.
Abeta 17-42 in Alzheimer's disease activates JNK and caspase-8 leading to neuronal apoptosis.
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DOI：
10.1093/brain/awf205
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发表时间：
2002-09
期刊：
影响因子：
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通讯作者：
Wanli Wei;D. Norton;Xiantao Wang;J. Kusiak
中科院分区：
文献类型：
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作者：
Wanli Wei;D. Norton;Xiantao Wang;J. Kusiak
由α-和γ-分泌酶裂解淀粉样前体蛋白（APP）衍生的p3肽[淀粉样β-肽（Abeta）17-40/42]是阿尔茨海默病中弥漫性斑块和唐氏综合征中小脑前淀粉样蛋白的主要成分。然而，P3肽积累在阿尔茨海默病中的重要性及其毒性性质尚不清楚。在这里，我们证明了用Abeta 17-42处理细胞导致两种人神经母细胞瘤细胞系SH-SY 5 Y和IMR-32的凋亡。Abeta 17-42激活caspase-8和caspase-3，诱导聚（ADP-核糖）聚合酶裂解，但不激活caspase-9。选择性caspase-8和caspase-3抑制剂完全阻断Abeta 17-42诱导的神经元死亡。Abeta 17-42中度激活c-Jun N-末端激酶（JNK）;然而，SEK 1（JNK的上游激酶）的显性负突变体的过表达可保护Abeta 17-42诱导的神经元死亡。这些结果表明，Abeta 17-42通过Fas样/半胱天冬酶-8活化途径诱导神经元凋亡。我们的研究结果揭示了Abeta 17-42之前未被认识到的毒性作用。我们提出，Abeta 17-42构成了一个额外的毒性肽来源于APP蛋白水解，因此可能有助于阿尔茨海默病的神经元细胞损失的特点。
The p3 peptide [amyloid beta-peptide (Abeta) 17-40/42], derived by alpha- and gamma-secretase cleavage of the amyloid precursor protein (APP), is a major constituent of diffuse plaques in Alzheimer's disease and cerebellar pre-amyloid in Down's syndrome. However, the importance of p3 peptide accumulation in Alzheimer's disease and its toxic properties is not clear. Here, we demonstrate that treatment of cells with Abeta 17-42 leads to apoptosis in two human neuroblastoma cell lines, SH-SY5Y and IMR-32. Abeta 17-42 activated caspase-8 and caspase-3, induced poly(ADP-ribose) polymerase cleavage, but did not activate caspase-9. Selective caspase-8 and caspase-3 inhibitors completely blocked Abeta 17-42-induced neuronal death. Abeta 17-42 moderately activated c-Jun N-terminal kinase (JNK); however, overexpression of a dominant-negative mutant of SEK1, the upstream kinase of JNK, protected against Abeta 17-42 induced neuronal death. These results demonstrate that Abeta 17-42 induced neuronal apoptosis via a Fas-like/caspase-8 activation pathway. Our findings reveal the previously unrecognized toxic effect of Abeta 17-42. We propose that Abeta 17-42 constitutes an additional toxic peptide derived from APP proteolysis and may thus contribute to the neuronal cell loss characteristic of Alzheimer's disease.