Humanin and Colivelin: Neuronal-Death-Suppressing Peptides for Alzheimer's Disease and Amyotrophic Lateral Sclerosis

Masaaki Matsuoka, Yuichi Hashimoto, Sadakazu Aiso, Ikuo Nishimoto
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Abstract

Humanin (HN), a 24-amino-acid neuroprotective peptide, was originally found in the occipital lobe of an autopsied Alzheimer's disease (AD) patient. HN inhibits neuronal death by binding to its specific receptor on the cell membrane and triggering a Jak2/STAT3 prosurvival pathway. The activation of this pathway may represent a therapeutic approach to AD. HN also exhibits neuroprotective activity against toxicity by familial amyotrophic lateral sclerosis (ALS)-related mutant superoxide dismutase (SOD1). Recent investigations established that AGA-(C8R)-HNG17, a 17-amno-acid derivative of HN, is 105 times more potent as a neuroprotective than HN; at 10-picomolar and higher concentrations in vitro it completely suppresses neuronal death. Moreover, a 26-amino-acid peptide colivelin (CL), composed of activity-dependent neurotrophic factor (ADNF) C-terminally fused to AGA-(C8R)-HNG17, provides complete neuroprotection at 100-femtomolar or higher concentrations in vitro. A series of experiments using mouse AD and ALS models further established the efficacy of HN derivatives, including CL, against these diseases in vivo. HN and CL can be viewed as drug candidates for neuronal death suppression therapy in AD or ALS.

人蛋白和Colivelin:阿尔茨海默病和肌萎缩侧索硬化症的神经元死亡抑制肽
Humanin (HN)是一种由24个氨基酸组成的神经保护肽,最初是在一名阿尔茨海默病(AD)尸检患者的枕叶中发现的。HN通过结合其在细胞膜上的特异性受体并触发Jak2/STAT3促存活通路来抑制神经元死亡。激活这一途径可能是一种治疗AD的方法。HN还表现出抗家族性肌萎缩性侧索硬化症(ALS)相关突变体超氧化物歧化酶(SOD1)毒性的神经保护活性。最近的研究证实,HN的17-氨基酸衍生物AGA-(C8R)- hng17的神经保护作用是HN的105倍;在10皮摩尔及更高的体外浓度下,它完全抑制神经元死亡。此外,一种由活性依赖性神经营养因子(ADNF) c末端融合到AGA-(C8R)- hng17的26氨基酸肽colivelin (CL)在体外提供100飞摩尔或更高浓度的完全神经保护。利用小鼠AD和ALS模型进行的一系列实验进一步证实了HN衍生物(包括CL)在体内对这些疾病的治疗作用。HN和CL可被视为AD或ALS神经元死亡抑制治疗的候选药物。
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