Alzheimer’s Study Finds a Target in a Stress Neurotransmitter

University of California researchers recently showed that the targeting of a neurotransmitter involved in stress responses significantly reduced cellular and tissue damage while preventing the onset of cognitive impairment in a transgenic mice model of Alzheimer’s disease. The study, entitled “Corticotropin-releasing factor receptor-1 antagonism mitigates beta amyloid pathology and cognitive and synaptic deficits in a mouse model of Alzheimer’s disease,” was published online in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

Previous research has implicated stress signaling pathways and corticotropin-releasing factor (CRF) in the pathogenesis of Alzheimer’s disease (AD). It has also been demonstrated that CRF is dysregulated in AD, leading to molecular changes in tau protein and higher production of amyloid-beta protein, forming plaques responsible for impaired cognition and progressive neurodegeneration. Furthermore, previous work has shown that CRF and its receptors are involved in another important process in AD, tau phosphorylation, confirming its mechanistic implication in pathogenicity.

Despite these findings, the molecules that target CRF pathways have not been fully explored or tested for their long-term efficacy and safety in animal models.

In this study, researchers used an established mouse model to explore the potential of type-1 corticotropin-releasing factor receptor (CRFR1) as a therapeutic target in the treatment of AD, using R121919, a CRF-antagonist (blocking the receptor) originally designed to treat anxiety disorders and irritable bowel syndrome. The scientists treated the 30-day-old AD transgenic mice with the antagonist small molecule for five months, and then examined behavioral and pathogenic disease markers. Results showed that the drug was able to reduce cellular and synaptic damage, possibly through reduction of amyloid plaques. Behavioral indicators of AD were also absent, and researchers reported no tolerability or safety issues.

In the future, the researchers want to design new assays that might lead to CRF receptor-1 antagonists for use in early phase human clinical trials of treatment safety.

“More work remains to be done, but this is the kind of basic research that is fundamental to ultimately finding a way to cure — or even prevent — Alzheimer’s disease,” David Brenner, MD, Vice Chancellor at UC San Diego Health Sciences and Dean of UCSD School of Medicine, said in a press release. “These findings … suggest we are on the cusp of creating truly effective therapies.”