Chiba Tomohiro, Yamada Marina, Hashimoto Yuichi, Sato Maiko, Sasabe Jumpei, Kita Yoshiko, Terashita Kenzo, Aiso Sadakazu, Nishimoto Ikuo, Matsuoka Masaaki
Department of Pharmacology, Keio University School of Medicine, Tokyo 160-8582, Japan.
J Neurosci. 2005 Nov 2;25(44):10252-61. doi: 10.1523/JNEUROSCI.3348-05.2005.
Alzheimer's disease (AD) is the most common cause of dementia. Humanin (HN) is a short bioactive peptide abolishing neuronal cell death induced by various familial AD (FAD)-causative genes and amyloid-beta (Abeta) in vitro. It has been shown that HN suppresses memory impairment of mice induced by intracerebroventricular administration of Abeta. To potentiate the neuroprotective effect of HN, we synthesized a hybrid peptide named Colivelin composed of activity-dependent neurotrophic factor (ADNF) C-terminally fused to AGA-(C8R)HNG17, a potent HN derivative. Colivelin completely suppresses death induced by overexpressed FAD-causative genes and Abeta1-43 at a concentration of 100 fM, whereas AGA-(C8R)HNG17 does so at a concentration of 10 pM. Colivelin-induced neuroprotection has been confirmed to occur via two neuroprotective pathways: one mediated by Ca2+/calmodulin-dependent protein kinase IV, triggered by ADNF, and one mediated by signal transducer and activator of transcription 3, triggered by HN. In vivo animal studies have further indicated that intracerebroventricular administration of Colivelin not only completely suppresses impairment in spatial working memory induced by repetitive intracerebroventricular injection of Abeta25-35 or Abeta1-42, but also it antagonizes neuronal loss in the CA1 region of hippocampus induced by hippocampal injection of Abeta1-42. In addition, intraperitoneally administered Colivelin suppresses memory impairment caused by a muscarinic acetylcholine receptor antagonist, 3-quinuclidinyl benzilate, indicating that a substantial portion of intraperitoneally administered Colivelin passes through the blood-brain barrier and suppresses functional memory deficit. Thus, Colivelin might serve as a novel drug candidate for treatment of AD.
阿尔茨海默病（AD）是痴呆最常见的病因。人胰岛素（HN）是一种短生物活性肽，在体外可消除由各种家族性AD（FAD）致病基因和β-淀粉样蛋白（Aβ）诱导的神经元细胞死亡。研究表明，HN可抑制脑室内注射Aβ诱导的小鼠记忆损伤。为增强HN的神经保护作用，我们合成了一种名为Colivelin的杂合肽，它由活性依赖神经营养因子（ADNF）与AGA-(C8R)HNG17（一种有效的HN衍生物）的C末端融合而成。Colivelin在浓度为100 fM时可完全抑制由过表达的FAD致病基因和Aβ1-43诱导的细胞死亡，而AGA-(C8R)HNG17在浓度为10 pM时才能做到。已证实Colivelin诱导的神经保护作用通过两条神经保护途径发生：一条由ADNF触发，通过Ca2+/钙调蛋白依赖性蛋白激酶IV介导；另一条由HN触发，通过信号转导和转录激活因子3介导。体内动物研究进一步表明，脑室内注射Colivelin不仅能完全抑制重复脑室内注射Aβ25-35或Aβ1-42诱导的空间工作记忆损伤，还能拮抗海马注射Aβ1-42诱导的海马CA1区神经元丢失。此外，腹腔注射Colivelin可抑制毒蕈碱型乙酰胆碱受体拮抗剂3-喹核醇苯甲酸酯引起的记忆损伤，这表明腹腔注射的Colivelin有很大一部分穿过血脑屏障并抑制功能性记忆缺陷。因此，Colivelin可能是一种治疗AD的新型候选药物。
