title: 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.
abstract: 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.
authors.affiliation: Department of Pharmacology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Chiba
authors.forename: Marina
authors.initials: M
authors.lastname: Yamada
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Maiko
authors.initials: M
authors.lastname: Sato
authors.forename: Jumpei
authors.initials: J
authors.lastname: Sasabe
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Kita
authors.forename: Kenzo
authors.initials: K
authors.lastname: Terashita
authors.forename: Sadakazu
authors.initials: S
authors.lastname: Aiso
authors.forename: Ikuo
authors.initials: I
authors.lastname: Nishimoto
authors.forename: Masaaki
authors.initials: M
authors.lastname: Matsuoka
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology / Q000517:prevention & control*; D000595:Amino Acid Sequence; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D047908:Intracellular Signaling Peptides and Proteins / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000737:chemistry; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics; D010455:Peptides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000235:genetics; D051381:Rats
chemical_list: C508523:Colivelin; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010455:Peptides; C427211:humanin