Cheng Zhang1, Ching-Chang Kuo2, Setareh H Moghadam1, Louise Monte1, Shannon N Campbell1, Kenner C Rice3, Paul E Sawchenko4, Eliezer Masliah5, Robert A Rissman6. 1. Department of Neurosciences, University of California San Diego, La Jolla, CA, USA. 2. NeuroInformatics Center, University of Oregon, Eugene, OR, USA. 3. Chemical Biology Research Branch, National Institute on Drug Abuse and Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA. 4. Salk Institute for Biological Studies, La Jolla, CA, USA. 5. Department of Neurosciences, University of California San Diego, La Jolla, CA, USA; Department of Pathology, University of California San Diego, La Jolla, CA, USA. 6. Department of Neurosciences, University of California San Diego, La Jolla, CA, USA. Electronic address: rrissman@ucsd.edu.
Abstract
INTRODUCTION: 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. METHODS: 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. RESULTS: 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. DISCUSSION: CRFR1 antagonism presents a viable disease-modifying therapy for AD, recommending its advancement to early-phase human safety trials.
INTRODUCTION: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. METHODS: 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 ADtransgenic mice with the small-molecule, CRFR1-selective antagonist, R121919, for 5 months, and examined AD pathologic and behavioral end points. RESULTS: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. DISCUSSION: CRFR1 antagonism presents a viable disease-modifying therapy for AD, recommending its advancement to early-phase human safety trials.
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