title: Corticotropin-releasing factor receptor-1 antagonism mitigates beta amyloid pathology and cognitive and synaptic deficits in a mouse model of Alzheimer's disease.
abstract: Stress and corticotropin-releasing factor (CRF) have been implicated as mechanistically involved in Alzheimer's disease (AD), but agents that impact CRF signaling have not been carefully tested for therapeutic efficacy or long-term safety in animal models.
  
  
  
  To test whether antagonism of the type-1 corticotropin-releasing factor receptor (CRFR1) could be used as a disease-modifying treatment for AD, we used a preclinical prevention paradigm and treated 30-day-old AD transgenic mice with the small-molecule, CRFR1-selective antagonist, R121919, for 5 months, and examined AD pathologic and behavioral end points.
  
  
  
  R121919 significantly prevented the onset of cognitive impairment in female mice and reduced cellular and synaptic deficits and beta amyloid and C-terminal fragment-β levels in both genders. We observed no tolerability or toxicity issues in mice treated with R121919.
  
  
  
  CRFR1 antagonism presents a viable disease-modifying therapy for AD, recommending its advancement to early-phase human safety trials.
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: NeuroInformatics Center, University of Oregon, Eugene, OR, USA.
authors.forename: Ching-Chang
authors.initials: CC
authors.lastname: Kuo
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: Setareh H
authors.initials: SH
authors.lastname: Moghadam
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: Louise
authors.initials: L
authors.lastname: Monte
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: Shannon N
authors.initials: SN
authors.lastname: Campbell
authors.affiliation: Chemical Biology Research Branch, National Institute on Drug Abuse and Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.affiliation: Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Sawchenko
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA; Department of Pathology, University of California San Diego, La Jolla, CA, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA. Electronic address: rrissman@ucsd.edu.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Rissman
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003071:Cognition / Q000502:physiology*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D011743:Pyrimidines; D018019:Receptors, Corticotropin-Releasing Hormone / Q000172:deficiency / Q000235:genetics; D013569:Synapses / Q000378:metabolism*; D000099052:CRF Receptor, Type 1
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D011743:Pyrimidines; C412383:R 121919; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1
keywords: Alzheimer's disease; Beta amyloid; Cognitive deficits; Corticotropin-releasing factor receptor; Corticotropin-releasing hormone; Hippocampus; R121919; Stress; Synaptic deficits