Cytotoxic mechanisms by M239V presenilin 2, a little-analyzed Alzheimer's disease causative mutant
Cytotoxic mechanisms by M239V presenilin 2, a little-analyzed Alzheimer's disease causative mutant
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DOI：
10.1002/jnr.20163
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发表时间：
2004-08-15
影响因子：
4.2
通讯作者：
Nishimoto, I
中科院分区：
文献类型：
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作者：
Abe, Y;Hashimoto, Y;Nishimoto, I
尽管早老素（PS）2的家族性阿尔茨海默病（FAD）相关N141 I突变体的神经毒性功能得到了很好的表征，但对另一种已确定的FAD致病突变体M239 V-PS2却知之甚少。我们发现M239 V-PS2的表达引起神经细胞毒性。M239 V-PS2表现出三种形式的细胞毒性：一种对抗氧化剂谷胱甘肽乙酯（GEE）和半胱天冬酶抑制剂Ac-DEVD-CHO（DEVD）均敏感;第二种对GEE敏感但对DEVD耐药;第三种对两者均耐药。M239 V-PS2的GEE/DEVD敏感性细胞毒性可能是通过NADPH氧化酶，而GEE敏感性/DEVD抗性细胞毒性可能是通过黄嘌呤氧化酶（XO）。M239 V-PS2的两种机制均被百日咳毒素（PTX）抑制，并且由Ga（o）介导，但不由Ga（i）介导。尽管Abeta 1 -43本身不诱导细胞毒性，但Abeta 1 -43增强了M239 V-PS2细胞毒性的所有三种组分。由于M239 V-PS2的这些细胞毒性机制与N14 I-PS2完全相同，因此它们最有可能涉及PS2突变引起的FAD的病理机制。值得注意的是，M239 V-PS2的细胞毒性可以通过两种临床上可用的超氧化物生成酶抑制剂夹竹桃苷和羟嘌呤醇的组合来抑制。(C)2004 Wiley-Liss，Inc.
Although neurotoxic functions are well characterized in familial Alzheimer's disease (FAD)-linked N141I mutant of presenilin (PS)2, little has been known about M239V-PS2, another established FAD-causative mutant. We found that expression of M239V-PS2 caused neuronal cytotoxicity. M239V-PS2 exerted three forms of cytotoxicity: one was sensitive to both an antioxidant glutathione-ethyl-ester (GEE) and a caspase inhibitor Ac-DEVD-CHO (DEVD); the second was sensitive to GEE but resistant to DEVD; and the third was resistant to both. The GEE/DEVD-sensitive cytotoxicity by M239V-PS2 was likely through NADPH oxidase and the GEE-sensitive/DEVD- resistant cytotoxicity through xanthine oxidase (XO). Both mechanisms by M239V-PS2 were suppressed by pertussis toxin (PTX) and were mediated by Galpha(o), but not by Galpha(i). Although Abeta1-43 itself induced no cytotoxicity, Abeta1-43 potentiated all three components of M239V-PS2 cytotoxicity. As these cytotoxic mechanisms by M239V-PS2 are fully shared with N14I-PS2, they are most likely implicated in the pathomechanism of FAD by PS2 mutations. Notably, cytotoxicity by M239V-PS2 could be inhibited by the combination of two clinically usable inhibitors of superoxide-generating enzymes, apocynin and oxypurinol. (C) 2004 Wiley-Liss, Inc.