Scientists Reveal Innovative Plan to Target the Cause of Alzheimer's Disease

Academics from the University of Cambridge and Lund University in Sweden have come up with the first strategy to "tackle" the cause of this devastating disease, hoping that new drugs could be developed to treat dementia.

Professor Michele Vendruscolo, one of the world's leading scientists, said, "This is the first time that a systematic method of controlling pathogens – the cause of Alzheimer's disease – is proposed. Recently, scientists have not been able to agree on the cause and so we have no target because the pathogens have been identified as small clumps of proteins known as oligomers. particles. "

Dementia is the leading cause of death in the UK and the cost of dementia is expected to more than double in the next 25 years, from 26 to 55 billion pounds. The global economy is estimated to cost nearly a trillion dollars each year.

Alzheimer's disease causes nerve cell death and tissue loss in the brain. Over time, the brain contracts dramatically and the destruction of cells causes memory failure, personality changes, and problems with daily activities.

Scientists have identified abnormal deposits called protein oligomers as the most likely suspects of the cause of dementia. Although proteins are normally responsible for important cellular processes, when people with Alzheimer's disease suffer from this disease, they become thugs, form clumps and destroy healthy nerve cells.

Proteins must fall back into a specific structure to function properly. When this folding process fails, the cell presents a serious problem of "folding" and dangerous deposits, which can cause dementia, can form and the brain can not get rid of them. Poorly folded proteins form abnormal clusters called plaques that accumulate between nerve cells and prevent them from reporting properly. Dying nerve cells also contain entanglements that are twisted protein strands that destroy a vital cell transport system, meaning that nutrients and other essential supplies can no longer circulate in the cells.

Prof. Vendruscolo explained, "A healthy brain has a quality control system that effectively removes the masses of potentially dangerous proteins called aggregates.As you get older, the brain becomes less able to get rid of the dangerous deposits leading to the disease. a home recycling system, if you have an effective system in place, the clutter is eliminated quickly, otherwise you accumulate slowly but regularly unnecessary waste. "

The research was conducted by an international team of scientists also including Professor Sir Christopher Dobson, Master of St John's College of Cambridge University, Center for Collapsed Disease (CMD), co-founded by Sir Christopher. Their research article was published today in the Proceedings of the National Academy of Sciences (PNAS).

Sir Christopher said, "This interdisciplinary study shows that it is possible not only to find compounds that target toxic oligomers that cause neurodegenerative disorders, but also to increase their potency in a rational way." to design molecules that have specific effects on different stages of disorders such as Alzheimer's disease and, hopefully, convert them into drugs that can be used in a clinical setting. "

Dementia costs the health and social services sector more than cancer and heart disease combined and receives a disproportionate investment in research – in 2012, dementia research in the United Kingdom received six times less

There have been about 400 clinical trials on Alzheimer's disease, but none of them specifically targeted the causative pathogens. In the United Kingdom, dementia is the only condition in the top 10 causes of death without treatment to prevent, cure or slow its progression.

Prof. Vendruscolo added: "All previous clinical trials to find drugs to change the disease have failed, the successful trials have given us a handful of medicines, but these drugs can only treat the symptoms of the disease. Alzheimer's start and progression Our research is based on the main conceptual step of identifying protein oligomers as pathogens and presents a method for systematically developing compounds to target them.

The drug discovery involves the screening of chemical banks, identifying the active ingredient from a natural remedy or design resulting in an understanding of the target, in this case the oligomers of proteins. The development includes additional studies, clinical trials and, ultimately, regulatory approval.

The team estimates that their first drug candidates could be tested in clinical trials in about two years. They co-founded Wren Therapeutics, a Cambridge biotechnology company, based in the new building of Health Chemistry, whose mission is to take the ideas developed at the University of Cambridge and translate them into new methods. diagnosis and treatment. disease and other folding disorders.

The group's new strategy is based on an innovative approach to chemical kinetics developed over the last decade by scientists led jointly by Professor Tuomas Knowles, also a professor at St John's College, Sir Christopher and Professor Vendruscolo at the new Cambridge Center. collaboration with scientists from Lund University led by Professor Sara Linse.

Prof. Knowles said, "We are very excited about the potential of chemical kinetics for the discovery of drugs against protein folding diseases.The aggregation process being very dynamic, the framework of kinetics allows us to stop the generation of toxic proteins at their very source. "

The advance was well received by leading medical experts.

Dr. David Reynolds, Scientific Director of Alzheimer's Research UK, said: "This is a detailed academic study on how quickly the compounds are able to" find out. To prevent amyloid from turning into toxic clusters, features of Alzheimer's disease or to stop diseases that cause dementia, it is vital to improve such approaches that could help improve progress. of drug discovery and accelerate new treatments for people living with Alzheimer's disease. "

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More information:
Sean Chia el al., "Kinetic SAR for drug discovery in protein folding diseases", PNAS (2018). www.pnas.org/cgi/doi/10.1073/pnas.1807884115