Corticotropin-releasing factor receptor-1 antagonism mitigates beta amyloid pathology and cognitive and synaptic deficits in a mouse model of Alzheimer's disease.

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.

• Authors: Cheng Zhang, Ching-Chang Kuo, Setareh H Moghadam, Louise Monte, Shannon N Campbell, Kenner C Rice, Paul E Sawchenko, Eliezer Masliah, Robert A Rissman
• Journal: Alzheimer's & dementia : the journal of the Alzheimer's Association (Alzheimers Dement) Vol. 12 Issue 5 Pg. 527-37 (05 2016) ISSN: 1552-5279 [Electronic] United States
• PMID: 26555315 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 Alzheimer's Association. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Pyrimidines
• R 121919
• Receptors, Corticotropin-Releasing Hormone
• CRF receptor type 1

Topics

• Alzheimer Disease (metabolism, pathology)
• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Animals
• Brain (metabolism, pathology)
• Cognition (physiology)
• Disease Models, Animal
• Humans
• Mice
• Mice, Transgenic
• Pyrimidines
• Receptors, Corticotropin-Releasing Hormone (deficiency, genetics)
• Synapses (metabolism)