Elucidation of molecular mechanisms for cell death in neurodegenerative diseases and extensive research of their antagonists

神经细胞死亡是阿尔茨海默病(AD)的中枢异常。因此，为了建立AD的根治疗法，控制神经细胞死亡是强制性的。AD治疗发展的一条重要线索是寻找通过家族性阿尔茨海默病(FAD)基因和Aβ淀粉样蛋白抑制神经细胞死亡的分子。通过基于疾病的死亡陷阱筛选，我们发现了一个新的基因，命名为人蛋白(HN)，它编码一个分泌型24个残基的多肽。HN可阻断所有已知的FAD基因APP、PS1、PS2和Aβ1-43引起的神经细胞死亡，而不影响亨廷顿病/脊髓小脑性共济失调相关聚谷氨酰胺重复序列Q79或肌萎缩侧索硬化症引起的SOD1突变体引起的神经细胞死亡。因此，HN是AD相关损伤所致神经细胞死亡的选择性和全能型抑制因子。HN的救治作用是通过抑制FAD基因的Aβ非依赖性和依赖性神经毒性而实现的，而对Aβ的产生没有任何影响，提示HN对AD相关的损伤具有完全补充Aβ产生抑制剂的拮抗作用。HN的拯救作用被C8A取消，而被S14G增强，使S14G HN在1000nM时完全活跃，对抗所有FAD基因和Aβ。这一新的因子HN及其衍生物将对AD的治疗方法的发展做出重大贡献。

Neuronal cell death is the central abnormality in Alzheimer's disease (AD). To establish curative therapy for AD, controlling neuronal cell death is therefore mandatory. An important clue in the development of AD therapy is to find the molecules that suppress neuronal cell death by familial Alzheimer's disease (FAD) genes and Aβ amyloid. Through disease-based death trap screening, we identified a novel gene, designated Humanin (HN) cDNA, which encodes a secretory 24 residue polypeptide. HN abolished death of neuronal cells by all known kinds of FAD genes-mutant APP, PS1 and PS2 and Aβ1-43 without effect on neuronal cell death by Huntington's disease/spinocerebellar ataxia-linked polyglutamine repeat Q79 or amyotrophic lateral sclerosis-causative SOD1 mutants. Therefore, HN is a selective and omnipotent suppressor of neuronal cell death caused by AD-relevant insults. The rescue action of HN was mediated by suppression of both Aβ-independent and -dependent neurotoxicities of FAD genes without any effect on Aβ production, suggesting that HN antagonizes against AD-relevant insults in a manner totally supplemental with Aβ-production inhibitors. The rescue action of HN was abolished by C8A, and potentiated by S14G, allowing S14G HN to be fully active at 1000 nM against all of the FAD genes and Aβ. This novel factor HN and its derivatives will contribute significantly to the development of curative therapy for AD.