Detailed characterization of neuroprotection by a rescue factor Humanin against various Alzheimer's disease-relevant insults
Detailed characterization of neuroprotection by a rescue factor Humanin against various Alzheimer's disease-relevant insults
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DOI：
10.1523/jneurosci.21-23-09235.2001
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发表时间：
2001-12-01
影响因子：
5.3
通讯作者：
Nishimoto, I
中科院分区：
文献类型：
--
作者：
Hashimoto, Y;Niikura, T;Nishimoto, I
新因子Humanin （HN）可拮抗多种家族性阿尔茨海默病（AD）基因[淀粉样前体蛋白（APP）、m146l -早老素（PS） 1和N141I-PS2突变体V642I和K595N/M596L （NL）突变体]以及对多聚谷氨酰胺重复Q79或超氧化物歧化酶1突变体无效的A β 1-43的神经毒性作用。在这里，我们报道了HN还可以通过其他AD相关的损伤来抑制神经毒性：其他家族AD基因（A617G-APP, L648P-APP, A246E-PS1, L286V-PS1， C410Y-PS1和H163R-PS1），抗APP抗体刺激APP，以及其他A β肽（A β 1-42和A β 25-35）。发现HN不能抑制谷氨酸或朊病毒片段的神经毒性，进一步表明其作用特异性。针对ad相关的损伤，通常指出cys8和Ser（14）的重要作用，并且从Pro(3)到Pro（19）的结构域负责HN的拯救作用，其中七个残基被证明是必不可少的。我们还比较了S14G HN （HNG）与活性依赖性神经营养因子、IGF-I或基本FGF在对抗各种ad相关损伤（V642I-APP、NL-APP、M146L-PS1、N141I-PS2和A β 1-43）方面的神经保护作用。虽然这些因子都能通过A β -43消除神经毒性，但只有HNG能通过所有因子消除细胞毒性。HN及其衍生肽可能为阿尔茨海默病的病理生理研究提供新的视角，并为开发各种形式阿尔茨海默病的治疗干预措施提供新的途径。
novel factor, termed Humanin (HN), antagonizes against neurotoxicity by various types of familial Alzheimer's disease (AD) genes [V642I and K595N/M596L (NL) mutants of amyloid precursor protein (APP), M146L-presenilin (PS) 1, and N141I-PS2] and by A beta1-43 with clear action specificity ineffective on neurotoxicity by polyglutamine repeat Q79 or superoxide dismutase 1 mutants. Here we report that HN can also inhibit neurotoxicity by other AD-relevant insults: other familial AD genes (A617G-APP, L648P-APP, A246E-PS1, L286V-PS1, C410Y-PS1, and H163R-PS1), APP stimulation by anti-APP antibody, and other A beta peptides (A beta1-42 and A beta 25-35). The action specificity was further indicated by the finding that HN could not suppress neurotoxicity by glutamate or prion fragment. Against the AD-relevant insults, essential roles of Cys 8 and Ser(14) were commonly indicated, and the domain from Pro(3) to Pro(19) was responsible for the rescue action of HN, in which seven residues turned out to be essential. We also compared the neuroprotective action of S14G HN (HNG) with that of activity-dependent neurotrophic factor, IGF-I, or basic FGF for the antagonism against various AD-relevant insults (V642I-APP, NL-APP, M146L-PS1, N141I-PS2, and A beta1-43). Although all of these factors could abolish neurotoxicity by A beta -43, only HNG could abolish cytotoxicities by all of them. HN and HN derivative peptides may provide a new insight into the study of AD pathophysiology and allow new avenues for the development of therapeutic interventions for various forms of AD.