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The Journal of Neuroscience, November 2, 2005, 25(44):10252-10261; doi:10.1523/JNEUROSCI.3348-05.2005

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Neurobiology of Disease
Development of a Femtomolar-Acting Humanin Derivative Named Colivelin by Attaching Activity-Dependent Neurotrophic Factor to Its N Terminus: Characterization of Colivelin-Mediated Neuroprotection against Alzheimer's Disease-Relevant Insults In Vitro and In Vivo

Tomohiro Chiba,1 * Marina Yamada,1,2 * Yuichi Hashimoto,1 Maiko Sato,1 Jumpei Sasabe,1,2 Yoshiko Kita,1 Kenzo Terashita,1 Sadakazu Aiso,2 Ikuo Nishimoto,1 and Masaaki Matsuoka1

Departments of 1Pharmacology and 2Anatomy, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan

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} (A{beta}) in vitro. It has been shown that HN suppresses memory impairment of mice induced by intracerebroventricular administration of A{beta}. 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 A{beta}1-43 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 A{beta}25-35 or A{beta}1-42, but also it antagonizes neuronal loss in the CA1 region of hippocampus induced by hippocampal injection of A{beta}1-42. 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.

Key words: Alzheimer's disease; APP; A{beta}; ADNF; Humanin; Colivelin

Received May 20, 2005; revised September 20, 2005; accepted September 23, 2005.






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