Modulating Brain's Stress Circuity Might Prevent Alzheimer's Disease Neuropathy

Previous research has shown a link between the brain's stress signaling pathways and Alzheimer's disease (AD). Long-term treatment using a small molecule drug that reduces activity of the brain's stress circuitry significantly reduces AD neuropathology and prevents onset of cognitive impairment in a mouse model of the neurodegenerative condition, revealed researchers at University of California and San Diego School of Medicine. The release of a stress-coping hormone called corticotropin-releasing factor (CRF), which is widely found in the brain and acts as a neurotransmitter/neuromodulator, is dysregulated in AD. It is associated with impaired cognition and with detrimental changes in tau protein and increased production of amyloid-beta - protein fragments that clump together and trigger the neurodegeneration characteristic of AD.

The study's principal investigator and corresponding author Robert Rissman, assistant professor in the Department of Neurosciences and Biomarker Core Director for the Alzheimer's Disease Cooperative Study (ADCS) said, "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 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 - and 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."

In other words, the research team determined that modulating the mouse brain's stress circuitry (without actually changing the normal response) mitigated generation and accumulation of amyloid plaques widely attributed with causing neuronal damage and death. As a consequence, behavioral indicators of AD were prevented and cellular damage was found to be reduced. The mice began treatment at 30-days-old - before any pathological or cognitive signs of AD were present - and continued until six months of age.

Rissman said, "One particular challenge is limiting exposure of the drug to the brain so that it does not impact the body's ability to response to stress. This can be accomplished because one advantage of these types of small molecule drugs is that they readily cross the blood-brain barrier and actually prefer to act in the brain."

Drugs like R121919 were originally designed to treat generalized anxiety disorder, irritable bowel syndrome (IBS) and other diseases, but failed to be effective in treating those disorders.

William Mobley, chair of the Department of Neurosciences and interim co-director of the Alzheimer's Disease Cooperative Study at UC San Diego, said, "Rissman's prior work demonstrated that CRF and its receptors are integrally involved in changes in another AD hallmark, tau phosphorylation. This new study extends those original mechanistic findings to the amyloid pathway and preservation of cellular and synaptic connections. Work like this is an excellent example of UC San Diego's bench-to-bedside legacy, whereby we can quickly move our basic science findings into the clinic for testing."

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Rissman said, "R121919 was well-tolerated by AD mice (no significant adverse effects) and deemed safe, suggesting CRF-antagonism is a viable, disease-modifying therapy for AD. Repurposing R121919 for human use was likely not possible at this point."

The team is collaborating with the Sanford Burnham Prebys Medical Discovery Institute to design new assays to discover the next generation of CRF receptor-1 antagonists for testing in early phase human safety trials.

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David Brenner, vice chancellor, UC San Diego Health Sciences and dean of UC San Diego School of Medicine, said, "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."

The study appears online in Alzheimer's & Dementia: The Journal of the Alzheimer's Association.

Source-Eurekalert