Skip to main content
Corticotropin-releasing factor receptor-1 antagonism mitigates beta amyloid pathology and cognitive and synaptic deficits in a mouse model of Alzheimer's disease.
- Author(s): Zhang, Cheng;
- Kuo, Ching-Chang;
- Moghadam, Setareh H;
- Monte, Louise;
- Campbell, Shannon N;
- Rice, Kenner C;
- Sawchenko, Paul E;
- Masliah, Eliezer;
- Rissman, Robert A
- et al.
Published Web Locationhttps://doi.org/10.1016/j.jalz.2015.09.007
IntroductionStress 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.
MethodsTo 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.
ResultsR121919 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.
DiscussionCRFR1 antagonism presents a viable disease-modifying therapy for AD, recommending its advancement to early-phase human safety trials.
For improved accessibility of PDF content, download the file to your device.