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

神经元细胞死亡是阿尔茨海默病（AD）的中心异常。因此，为了建立AD的治愈性疗法，控制神经元细胞死亡是强制性的。寻找家族性阿尔茨海默病（FAD）基因和Aβ淀粉样蛋白抑制神经元细胞死亡的分子是AD治疗发展的一条重要线索。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Humanin（HN）cDNA，它编码一个分泌型24个残基的多肽。HN消除了所有已知类型的FAD基因突变的APP、PS1和PS2以及Aβ1-43引起的神经元细胞死亡，而对亨廷顿病/脊髓小脑共济失调相关的多聚谷氨酰胺重复序列Q79或肌萎缩性侧索硬化症引起的SOD 1突变体引起的神经元细胞死亡没有影响。因此，HN是一种选择性的和全能的抑制神经元细胞死亡所造成的AD相关的侮辱。HN的拯救作用是通过抑制FAD基因的Aβ非依赖性和A β依赖性神经毒性而介导的，而对Aβ产生没有任何影响，表明HN以完全补充Aβ产生抑制剂的方式拮抗AD相关损伤。HN的拯救作用被C8 A消除，并被S14 G增强，使S14 G HN在1000 nM时对所有FAD基因和Aβ具有完全活性。这种新的因子HN及其衍生物将有助于AD治疗的发展。

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.