Alzheimer's disease cure: reducing the brain's stress circuitry may help prevent the disease

Alzheimer's disease affects about 5.1 million people in the United States alone, the Alzheimer's Foundation of America reports. According to the CDC, it is the most common form of dementia and is one of the top 10 leading causes of death in the United States.

A recent study coming from researchers at the University of California, San Diego School of Medicine has shown that a small molecule drug called R121919, which reduces the brain's stress circuitry, may significantly lessen Alzheimer's disease (AD) neuropathology and also prevents the onset of cognitive impairment, Eurekalert reports.

Previous research has shown the relationship between the brain's stress signaling pathways and Alzheimer's disease. In fact, the neurotransmitter/neuromodulator that is the tress-coping hormone called corticotropin-releasing factor (CRF) is often unregulated in people who have Alzheimer's disease, and is also linked with impaired cognition.

Science Daily reports that for the study, researchers created a novel animal study design that mimicked human clinical trials. Researchers found that modulating a mouse brain's stress circuitry alone decreased the generation and accumulation of amyloid plaques that cause neuronal damage and death. As a result, behavioral indicators of Alzheimer's disease were prevented and cellular damage was lessened.

"Our work and that of our colleagues on stress and CRF have been mechanistically implicated in Alzheimer’s disease, but agents that impact CRF signaling have not been carefully tested for therapeutic efficacy or long-term safety in animal models," the study's principal investigator and corresponding author Robert Rissman, PhD said in a UCSD Health Sciences press release.

"The novelty of this study is two-fold: We used a preclinical prevention paradigm of a CRF-antagonist (a drug that blocks the CRF receptor in brain cells) called R121919 in a well-established AD model," he explained. "We did so in a way that draws upon our experience in human trials. We found that R121919 antagonism of CRF-receptor-1 prevented onset of cognitive impairment and synaptic/dendritic loss in AD mice."

Results have shown that the drug was well tolerated by the mice who had Alzheimer's disease, showing no significant adverse effects. However, Rissman noted that repurposing the R121919 drug for human use wasn't possible at this time, so they are working with the Sanford Burnham Prebys Medical Discovery Institute to discover the next generation of CRF receptor-1 antagonists for testing in humans.

David Brenner, MD, vice chancellor, UC San Diego Health Sciences and dean of UC San Diego School of Medicine commented that "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. These findings by Dr. Rissman and his colleagues at UC San Diego and at collaborating institutions on the Mesa suggest we are on the cusp of creating truly effective therapies."