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CRF receptor-1 antagonism mitigates Aβ pathology and cognitive and synaptic deficits in a mouse model of Alzheimer's disease


Year of Publication:
Contact PI Name:
Robert A. Rissman
Contact PI Affiliation:
Department of Neurosciences, University of California San Diego, La Jolla, California, USA
Cheng Zhang, Ching-Chang Kuo, Setareh H. Moghadam, Louise Monte, Shannon N. Campbell, Kenner C. Rice, Paul E. Sawchenko, Eliezer Masliah
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Alzheimer's Association
Alzheimer's Art Quilt Initiative
Clayton Medical Research Foundation
The Leona M. and Harry B. Helmsley Charitable Trust
Study Goal and Principal Findings:

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. 

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Corticotropin-Releasing Factor Receptor 1 (CRFR1)
Therapeutic Notes:
Corticotropin-Releasing Factor Receptor 1 (CRFR1) has been nominated as a potential target for AD. Nominated targets are obtained from several sources, including the National Institute on Aging's Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) consortium. Targets have been identified using computational analyses of high-dimensional genomic, proteomic and/or metabolomic data derived from human samples. See Agora link for more information.

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Morris Water Maze
beta Amyloid Load
APP-CTF83 (CTF alpha)
APP-CTF99 (CTF beta)
beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Activity
Brain-Buffer Soluble beta Amyloid Peptide 40
Brain-Buffer Soluble beta Amyloid Peptide 42
Brain-Buffer Soluble beta Amyloid Peptide 38
Brain-Detergent Soluble beta Amyloid Peptide 40
Brain-Detergent Soluble beta Amyloid Peptide 42
Brain-Detergent Soluble beta Amyloid Peptide 38
Microtubule-Associated Protein 2 (MAP2)
Target Engagement (Binding to Corticotropin-Releasing Factor Receptors)
Liver Enzymes
Liver Morphology
Body Weight
Grooming Behavior