UCSD team targeting new stress pathway in Alzheimer's program

Alzheimer's has long been one of the most frustrating targets in R&D. Despite repeated assurances from rival camps that toxic loads of amyloid beta and tau are likely causes of the diseases, no one is quite sure what is going on and clinical failures are routine. But investigators at UC San Diego School of Medicine say they have been garnering some preclinical clues that would suggest there could be a new pathway to follow in the clinic.

Following the idea that the brain's stress signaling circuitry may play a role in the development of the disease, the UCSD group centered on a hormone called corticotropin-releasing factor. CRF is a neuropeptide that triggers the behavioral and biologic responses to stress, which UC says has been associated with worsening cognition as well as the alteration of tau and the creation of a-beta.

The team found a way to block the CRF receptor in mouse models for the disease with an anti-anxiety and IBS drug called R121919. Cellular damage was reduced, the scientists say, while the behavioral changes associated with the disease were also avoided in the mice.

UCSD's Robert Rissman

"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," said Robert Rissman, an assistant professor in the Department of Neurosciences and Biomarker Core Director for the Alzheimer's Disease Cooperative Study, in a release. "We found that R121919 antagonism of CRF-receptor-1 prevented onset of cognitive impairment and synaptic/dendritic loss in AD mice."

The group followed up by saying that R121919 appeared to be a safe way to hit the stress pathway, but that it was unlikely that they could repurpose the drug specifically for Alzheimer's. Now the team plans to search for new drugs that can do the same thing, with an eye to getting into the clinic.

"Rissman's prior work demonstrated that CRF and its receptors are integrally involved in changes in another AD hallmark, tau phosphorylation," said Dr. William Mobley, chair of the Department of Neurosciences and interim co-director of the Alzheimer's Disease Cooperative Study at UC San Diego, in the release. "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."

- here's the release
- read the research abstract

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