title: Selecting for neurogenic potential as an alternative for Alzheimer's disease drug discovery.
abstract: Neurons die in Alzheimer's disease (AD) and are not effectively replaced. An alternative approach to maintain nerve cell number is to identify compounds that stimulate the proliferation of endogenous neural stem cells in old individuals to replace lost neurons. However, unless a neurogenic drug is also neuroprotective, the replacement of lost neurons will not be sufficient to stop disease progression.
  
  
  
  The neuroprotective AD drug candidate J147 is shown to enhance memory, improve dendritic structure, and stimulate cell division in germinal regions of the brains of very old mice. Based on the potential neurogenic potential of J147, a neuronal stem cell screening assay was developed to optimize derivatives of J147 for human neurogenesis.
  
  
  
  The best derivative of J147, CAD-031, maintains the neuroprotective and memory enhancing properties of J147, yet is more active in the human neural stem cell assays.
  
  
  
  The combined properties of neuroprotection, neurogenesis, and memory enhancement in a single drug are more likely to be effective for the treatment of age-associated neurodegenerative disorders than any individual activity alone.
authors.affiliation: The Salk Institute for Biological Studies, Cellular Neurobiology, La Jolla, CA, USA.
authors.forename: Marguerite
authors.initials: M
authors.lastname: Prior
authors.affiliation: The Salk Institute for Biological Studies, Cellular Neurobiology, La Jolla, CA, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Goldberg
authors.affiliation: The Salk Institute for Biological Studies, Cellular Neurobiology, La Jolla, CA, USA.
authors.forename: Chandramouli
authors.initials: C
authors.lastname: Chiruta
authors.affiliation: Behavior Testing Core, The Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Farrokhi
authors.affiliation: The Salk Institute for Biological Studies, Cellular Neurobiology, La Jolla, CA, USA.
authors.forename: Mariya
authors.initials: M
authors.lastname: Kopynets
authors.affiliation: Department of Molecular and Cellular Neurosciences, The Scripps Research Institute, La Jolla CA, USA.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Roberts
authors.affiliation: The Salk Institute for Biological Studies, Cellular Neurobiology, La Jolla, CA, USA. Electronic address: schubert@salk.edu.
authors.forename: David
authors.initials: D
authors.lastname: Schubert
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D003474:Curcumin / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D055808:Drug Discovery; D053595:Embryonic Stem Cells / Q000187:drug effects; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016222:Fibroblast Growth Factor 2; D003474:Curcumin
keywords: Aging; Alzheimer's disease; J147; Memory enhancement; Neurodegenerative disease; Neurogenesis; Neuroprotection; Stem cells