a novel neurotrophic drug for cognitive enhancement and alzheimers disease一种新型神经营养药物认知增强和阿尔茨海默氏症.pdfVIP

A Novel Neurotrophic Drug for Cognitive Enhancement and Alzheimer’s Disease 1. 1. 1 4 2,5 ´ 5 Qi Chen , Marguerite Prior , Richard Dargusch , Amanda Roberts , Roland Riek , Cedric Eichmann , 1 3 3 1 1 Chandramouli Chiruta , Tatsuhiro Akaishi , Kazuho Abe , Pamela Maher , David Schubert * 1 Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America, 2 Structural Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America, 3 Laboratory of Pharmacology, Research Institute of Pharmaceutical Sciences, Musashino University, Nishitokyo-shi, Tokyo, Japan, 4 Molecular Neurosciences, The Scripps Research Institute, La Jolla, California, United States of America, 5 Laboratorium f. Physikalische Chemie, ETH Zurich, Zurich, Switzerland Abstract Currently, the major drug discovery paradigm for neurodegenerative diseases is based upon high affinity ligands for single disease-specific targets. For Alzheimer’s disease (AD), the focus is the amyloid beta peptide (Aß) that mediates familial Alzheimer’s disease pathology. However, given that age is the greatest risk factor for AD, we explored an alternative drug discovery scheme that is based upon efficacy in multiple cell culture models of age-associated pathologies rather than exclusively amyloid metabolism. Using this approach, we identified an exceptionally potent, orally active, neurotrophic molecule that facilitates memory in normal rodents, and prevents the loss