Synapses connect nerve cells in our brains, and this is important to the formation of memories, however, these connections fail with this disease, and the brain cells die off. Accumulations of insoluble protein fibers called tau are one of the primary biomarkers of AD, in the brains of those with this disease tau accumulates in neurofibrillary tangles which kills the brain cells that are relied upon for memory, and as tau tangles continue to accumulate the symptoms of disease progress.
Researchers at Lancaster University used a special analytical Synchrotron Radiation Circular Dichroism technique to look at existing compounds of more than 80 existing compounds and drugs to determine their effectiveness against tau. They found that salbutamol, which contains epinephrine, was able to effectively stabilize the tau proteins and prevent them from forming tangles; when salbutamol was added to solutions containing tau the density of the tangles was observed to be drastically reduced.
“Our work highlights the potential impact of repurposing drugs for secondary medical uses, by discovering a novel therapeutic strategy that impedes the molecular pathology of Alzheimer’s disease, and which may have otherwise gone unstudied,” said Dr. David Townsend of Lancaster university, lead author of the study. “Salbutamol has already undergone extensive human safety reviews, and if follow up research reveals an ability to impede Alzheimer’s disease progression in cellular and animal models, this drug could offer a step forward, whilst drastically reducing the cost and time associated with typical drug development.”
However, the key ingredient epinephrine is rapidly metabolized in the human body rather than being absorbed, which is a problem. The next step of the research evaluated other available compounds with similar chemical structures which yielded the possible drug candidates including: etamivan, fenoterol, and dobutamine. Among these candidates dobutamine showed some promise with short lived effects, but also has the disadvantage of needing to be administered intravenously. While salbutamol is easily ingested, absorbed into the brain, and will remain active within the body for several hours making it more appealing.
Salbutamol has yet to be shown if it will have a helpful impact on tau tangles, but the researchers believe that it interacts with an early stage of tau fibril formation to reduce the ability to form an initial nucleus which drives the aggregation process.
This work follows 2018 research from Temple University published in the journal Molecular Neurobiology which found the asthma drug zileuton to have a desirable mitigating effect on tau in mice studies because it is a leukotriene inhibitor that decreases inflammation by preventing the inflammatory actions of leukotriene molecules.
“This work is in the very early stages and we are some way from knowing whether or not salbutamol will be effective at treating Alzheimer’s disease in human patients. However, our results justify further testing of salbutamol, and similar drugs, in animal models of the disease and eventually, if successful, in clinical trials,” said co-author Professor David Middleton of Lancaster University.
The effects of epinephrine on inflammation are still unknown. The researchers believe that further investigation into salbutamol and other asthma drugs as well as different methods of administering these drugs to be used against Alzheimer’s disease is well warranted.
