27 April 2015
University of Cambridge researchers have found that proteins that control the progression of Alzheimer’s are linked in a biological pathway, opening up the possibility that drugs targeting this pathway may be one way of treating the disease.
Alzheimer’s disease, a neurodegenerative condition, is the most common form of dementia. The exact cause is unknown, although we do know that beta-amyloid protein builds up in the brain forming characteristic amyloid plaques, and tau protein builds up to form neurofibrillary tangles; both disrupt the connections between neurons. Currently 500,000 people in the UK are affected by Alzheimer’s, which has no cure and few effective treatments.
Published in the journal Cell Reports, the research identified a new association between amyloid precursor protein (APP) and tau. The scientists found that as amyloid precursor protein (APP) is broken down into the harmful amyloid-beta fragments, this in turn affects changes in the way the protein tau behaves.
Previous research had found that following APP breakdown, rising amyloid-beta levels outside the cell trigger increased production of tau. However, the new research has revealed a second pathway that allows amyloid-beta to affect levels of tau whilst still inside the cell. The scientists used three classes of drugs that manipulated the rate at which APP was degraded, and observed that levels of tau were altered as well.
Despite the researchers identifying the pathway in neurons with the rarer familial form of Alzheimer’s, they found the same pathway exists in healthy neurons as well. This opens up the possibility that targeting the same pathway in the more common late-onset Alzheimer’s may be a way of treating the disease.
Lead researcher Dr Rick Livesey of the Wellcome Trust / Cancer Research UK Gordon Institute commented: “The questions is why hasn’t this pathway been identified, given that Alzheimer’s is so well studied…The answer is that mice don’t develop Alzheimer’s disease, and they don’t respond to these drugs the way human neurons do. It’s something we can only do by looking at real human neurons”.
Studying Alzheimer’s in a mice model of the disease, the researchers observed that immune cells that normally protect the brain instead begin to consume arginine, a vital amino acid. Going further, they found blocking the process with a small-molecule drug, difluromethylornithine (DFMO), prevented the characteristic brain plaques and memory loss in the mouse model of the disease.
However, the technique has only been tested in the mice model and cannot be guaranteed to work the same way in humans. Reflecting on the findings, head of research at the Alzheimer’s Society Dr James Pickett said: “Importantly, these new findings reflect earlier observations that arginine is reduced in the brains of people with Alzheimer’s disease…The next step would be to show that targeting arginine metabolism in the brain can reduce the death of brain cells, as this was not shown in the current study”.