Functional analysis of neuroprotective factor Humanin as a basis for Alzheimer's disease therapy

在阿尔茨海默病（AD）中，预防神经元细胞死亡应该会减缓疾病的进展。Humanin （HN）是一种24残基的神经保护肽（MAPRGFSCLLLLTSEIDLPVKRRA）。体外研究表明，HN保护神经元免受各种类型的ad相关损伤，包括淀粉样蛋白β肽和家族性ad相关的淀粉样前体蛋白和早老素突变。氨基酸替代研究表明，将Ser14替换为Gly （S14G-HN）在体外神经保护实验中显著提高了其作用效力：S14G-HN在1-10nM浓度下有效，而HN在1-10mM浓度下保护神经元。此外，S14G-HN通过脑室内注射改善淀粉样β诱导的记忆缺陷，而HN表现出相同的趋势，但无统计学意义。为了阐明HN和S14G-HN的作用机制，我们用圆二色性进行了二级结构分析。这些肽的二级结构在磷酸盐缓冲盐水中有显著差异。观察到S14G-HN的结构变化呈浓度和温度依赖关系，表明其通过疏水相互作用自缔合。

In Alzheimer's disease (AD), prevention of neuronal cell death should slow down the disease progression. Humanin (HN) is a 24-residue neuroprotective peptide (MAPRGFSCLLLLTSEIDLPVKRRA). In vitro studies showed that HN protected neurons from various types of AD-related insults, which include amyloid beta peptides and familial AD-linked mutants of amyloid precursor protein and presenilins. Amino acid replacement study revealed that the substitution of Ser14 to Gly (S14G-HN) drastically increased its action potency in vitro neuroprotection assays: S14G-HN is effective at 1-10nM of concentration whereas HN protects neurons at 1-10mM. Furthermore, S14G-HN ameliorated memory deficit induced by amylid beta by intracerebroventricular injection, while HN showed the same tendency that was not statistically significant. To elucidate action mechanism of HN and S14G-HN, we performed secondary structure analysis by circular dichroism. The secondary structure of these peptides was significantly different in phosphate-buffered saline. The structural change of S14G-HN was observed in a concentration and temperature-dependent manner, suggesting self-association via hydrophobic interaction.