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，控制神经元细胞死亡是建立AD治疗方法的必要条件。发现抑制家族性阿尔茨海默病（FAD）基因和β淀粉样蛋白引起的神经元细胞死亡的分子是阿尔茨海默病治疗发展的重要线索。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，该基因编码分泌24残基多肽。HN可消除所有已知FAD基因突变体APP、PS1、PS2和Aβ1-43引起的神经元细胞死亡，但对亨廷顿病/脊髓小脑共济失调相关的多聚谷氨酰胺重复Q79或肌萎缩侧索硬化引起的SOD1突变体引起的神经元细胞死亡无影响。因此，HN是ad相关损伤引起的神经元细胞死亡的选择性和全能抑制剂。HN的拯救作用是通过抑制FAD基因的a β非依赖性和依赖性神经毒性介导的，而不影响a β的产生，这表明HN以完全补充a β产生抑制剂的方式拮抗ad相关的损伤。C8A消除了HN的拯救作用，S14G增强了HN的作用，使S14G 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及其衍生物将对阿尔茨海默病治疗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.