Introduction Neurodegenerative diseases (NDDs) are a group of disorders in the central nervous system (CNS) characterized by progressive loss of neu- rons. Most NDDs are incurable and fatal; there is no effective therapy. Signs and symptoms of NDDs are the loss of function of the affected neuronal systems. For example, Alzheimer’s dis- ease (AD), the most common NDD, is character- ized by memory deficit and learning disability, the result of neuronal loss in the cerebral cortex. Amyotrophic lateral sclerosis (ALS), the most Molecular Neurobiology 55 Volume 35, 2007 Molecular Neurobiology Copyright © 2007 Humana Press Inc. All rights of any nature whatsoever reserved. ISSN 0893–7648/07/35(1): 55–84/$30.00 ISSN (Online) 1559–1182 Neuroprotection Against Neurodegenerative Diseases Development of a Novel Hybrid Neuroprotective Peptide Colivelin Tomohiro Chiba, * Ikuo Nishimoto, Sadakazu Aiso, and Masaaki Matsuoka * Department of Anatomy and Pharmacology, KEIO University School of Medicine, Shinjuku-ku, Tokyo, Japan Abstract Neuronal death is directly implicated in the pathogenesis of neurodegenerative diseases (NDDs). NDDs cannot be cured because the mechanisms underlying neuronal death are too com- plicated to be therapeutically suppressed. Neuroprotective factors, such as neurotrophins, certain growth factors, neurotrophic cytokines, and short neuroprotective peptides, support neuronal survival in both physiological and pathological conditions, suggesting that these factors may be good drug candidates for NDDs. We recently generated a novel neuroprotective peptide named Colivelin by attaching activity-dependent neurotrophic factor (ADNF) to the N-terminus of a potent Humanin derivative, AGA-(C8R)HNG17. HN was originally identified from an Alzheimer’s disease (AD) brain as an endogenous neuroprotective peptide that suppresses AD- relevant toxicity. Colivelin protects neurons from death relevant to NDDs by activating two inde- pendent prosurvival signals: an ADNF-mediated Ca 2+ /calmodulin-dependent protein kinase IV pathway and an HN-mediated STAT3 pathway. The neuroprotective effect of Colivelin provides novel insights into therapy for NDDs. Index Entries: Colivelin; humanin; ADNF; neuronal death; neuroprotection; neurodegenerative diseases. Received July 7, 2006; Accepted August 7, 2006. * Authors to whom correspondence and reprint requests should be addressed. E-mail: chibat@sc.itc. keio.ac.jp, sakimatu@sc.itc.keio.ac.jp