Hashimoto Yuichi, Tsuji Osahiko, Niikura Takako, Yamagishi Yohichi, Ishizaka Miho, Kawasumi Masaoki, Chiba Tomohiro, Kanekura Kohsuke, Yamada Marina, Tsukamoto Emi, Kouyama Keisuke, Terashita Kenzo, Aiso Sadakazu, Lin Anning, Nishimoto Ikuo
Departments of Pharmacology and Anatomy, KEIO University School of Medicine, 35 Shinanomachi, Tokyo 160-8582, Japan.
J Neurochem. 2003 Feb;84(4):864-77. doi: 10.1046/j.1471-4159.2003.01585.x.
Amyloid precursor protein (APP), the precursor of Abeta, has been shown to function as a cell surface receptor that mediates neuronal cell death by anti-APP antibody. The c-Jun N-terminal kinase (JNK) can mediate various neurotoxic signals, including Abeta neurotoxicity. However, the relationship of APP-mediated neurotoxicity to JNK is not clear, partly because APP cytotoxicity is Abeta independent. Here we examined whether JNK is involved in APP-mediated neuronal cell death and found that: (i) neuronal cell death by antibody-bound APP was inhibited by dominant-negative JNK, JIP-1b and SP600125, the specific inhibitor of JNK, but not by SB203580 or PD98059; (ii) constitutively active (ca) JNK caused neuronal cell death and (iii) the pharmacological profile of caJNK-mediated cell death closely coincided with that of APP-mediated cell death. Pertussis toxin (PTX) suppressed APP-mediated cell death but not caJNK-induced cell death, which was suppressed by Humanin, a newly identified neuroprotective factor which inhibits APP-mediated cytotoxicity. In the presence of PTX, the PTX-resistant mutant of Galphao, but not that of Galphai, recovered the cytotoxic action of APP. These findings demonstrate that JNK is involved in APP-mediated neuronal cell death as a downstream signal transducer of Go.
淀粉样前体蛋白（APP）是β淀粉样蛋白（Aβ）的前体，已被证明可作为一种细胞表面受体，通过抗APP抗体介导神经元细胞死亡。c-Jun氨基末端激酶（JNK）可介导多种神经毒性信号，包括Aβ神经毒性。然而，APP介导的神经毒性与JNK之间的关系尚不清楚，部分原因是APP细胞毒性不依赖于Aβ。在此，我们研究了JNK是否参与APP介导的神经元细胞死亡，结果发现：（i）显性负性JNK、JIP-1b和JNK特异性抑制剂SP600125可抑制抗体结合的APP诱导的神经元细胞死亡，而SB203580或PD98059则无此作用；（ii）组成型激活（ca）JNK可导致神经元细胞死亡；（iii）caJNK介导的细胞死亡的药理学特征与APP介导的细胞死亡密切相符。百日咳毒素（PTX）可抑制APP介导的细胞死亡，但不能抑制caJNK诱导的细胞死亡，而新发现的神经保护因子Humanin可抑制APP介导的细胞毒性，从而抑制caJNK诱导的细胞死亡。在PTX存在的情况下，Gαo的PTX抗性突变体可恢复APP的细胞毒性作用，而Gαi的PTX抗性突变体则不能。这些发现表明，JNK作为Gαo的下游信号转导分子参与了APP介导的神经元细胞死亡。
