In novel mouse study, drug significantly prevented onset of cognitive and cellular effects
Researchers at the University of California, San Diego School of Medicine report that long-term treatment with a small-molecule drug that dampens the brain’s stress circuitry markedly reduces Alzheimer’s disease (AD) neuropathology and prevents the onset of cognitive impairment in a validated mouse model. The study used a preclinical design modeled on human clinical trials and found meaningful reductions in amyloid pathology, preservation of synapses and improved behavioral outcomes.
The results appear in the online edition of Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.
Alzheimer’s disease is multifactorial, driven by a mix of genetic, lifestyle and environmental factors. Growing evidence has linked dysregulated stress signaling in the brain to AD progression. Corticotropin-releasing factor (CRF), a stress-related neurotransmitter and hormone, is altered in AD and has been associated with impaired cognition, increased tau phosphorylation and elevated production of amyloid-beta peptides—protein fragments that aggregate into the plaques that contribute to neuronal dysfunction and degeneration.
Robert Rissman, PhD, assistant professor in the Department of Neurosciences and Biomarker Core Director for the Alzheimer’s Disease Cooperative Study (ADCS) at UC San Diego, led the investigation. He noted that while CRF signaling has been mechanistically implicated in AD, agents that target CRF pathways had not been systematically evaluated for therapeutic value and long-term safety in animal models.
“We applied a prevention paradigm using a CRF-receptor-1 antagonist, R121919, in a well-established AD mouse model and followed a study design informed by human clinical trials,” Rissman said. “Antagonism of the CRF receptor-1 prevented the development of cognitive deficits and reduced synaptic and dendritic loss in treated mice.”
The team administered R121919 beginning at 30 days of age—before pathological or cognitive signs were present—and continued treatment until the mice were six months old. The compound selectively blocks CRF receptor-1 (CRFR1), modulating stress-circuit activity in the brain without abolishing normal stress responses. Because these small molecules cross the blood-brain barrier and preferentially act in the central nervous system, the researchers were able to limit peripheral effects that could interfere with normal bodily stress responses.
Across multiple outcome measures, R121919 produced protective effects. Female mice showed significant prevention of cognitive impairment, while both male and female mice exhibited reduced beta-amyloid levels, lower C-terminal fragment-β levels, and preservation of synaptic and cellular integrity. Importantly, the treatment was well tolerated with no notable toxicity or adverse effects observed in the animals during the study period.
These findings extend prior work linking CRF signaling to tau pathology by demonstrating that CRFR1 antagonism also impacts the amyloid pathway and helps maintain neuronal connections. William Mobley, MD, PhD, chair of the Department of Neurosciences and interim co-director of the ADCS at UC San Diego, highlighted the translational potential: “This study connects mechanistic discoveries to disease-modifying outcomes, illustrating the bench-to-bedside approach that can accelerate development of new therapies.”
Although R121919 showed efficacy and safety in mice, Rissman indicated that repurposing this specific compound for human treatment may not be feasible at present. The research team is collaborating with the Sanford Burnham Prebys Medical Discovery Institute to develop new assays and to discover next-generation CRFR1 antagonists suitable for early-phase human safety trials.
David Brenner, MD, vice chancellor of UC San Diego Health Sciences and dean of the UC San Diego School of Medicine, emphasized the importance of continued basic research: “This is the kind of foundational work that ultimately brings us closer to preventing or curing Alzheimer’s disease. The findings suggest we are making progress toward genuinely effective, disease-modifying therapies.”
Co-authors on the study include Cheng Zhang, Setareh H. Moghadam, Louise Monte, Shannon N. Campbell and Eliezer Masliah (UC San Diego); Ching-Chang Kuo (University of Oregon); Kenner C. Rice (National Institute on Drug Abuse and Alcohol Abuse and Alcoholism); and Paul E. Sawchenko (Salk Institute for Biological Studies).
Funding: The research received support from the National Institutes of Health (grants AG032755, AG047484, DK026741, and AG010483), the Alzheimer’s Art Quilt Initiative, the Alzheimer’s Association, The Leona M. and Harry B. Helmsley Charitable Trust and the Clayton Medical Research Foundation.
Source: Scott LaFee, UCSD
Image credit: Public domain
Abstract summary
Title: Corticotropin-releasing factor receptor-1 antagonism mitigates beta amyloid pathology and cognitive and synaptic deficits in a mouse model of Alzheimer’s disease
Introduction: Stress and corticotropin-releasing factor (CRF) are implicated in Alzheimer’s disease. Until now, CRF-signaling modulators had not been thoroughly tested for therapeutic benefit or long-term safety in AD animal models.
Methods: Using a prevention-focused preclinical paradigm, investigators treated 30-day-old AD transgenic mice with the CRFR1-selective antagonist R121919 for five months and assessed behavioral and pathological endpoints relevant to AD.
Results: Treatment with R121919 significantly prevented cognitive decline in female mice, reduced synaptic and cellular deficits, and lowered beta-amyloid and C-terminal fragment-β levels in both sexes. No tolerability or toxicity problems were observed in treated animals.
Discussion: CRFR1 antagonism represents a promising disease-modifying strategy for Alzheimer’s disease and supports advancing CRF receptor-1 blockers toward early-phase human safety trials.
Study citation: Cheng Zhang, Ching-Chang Kuo, Setareh H. Moghadam, Louise Monte, Shannon N. Campbell, Kenner C. Rice, Paul E. Sawchenko, Eliezer Masliah, and Robert A. Rissman. Published online November 7, 2015. doi:10.1016/j.jalz.2015.09.007