Treatments to stop alzheimer's step closer as scientists discover key inhibitor molecule


Treatments to stop alzheimer's step closer as scientists discover key inhibitor molecule

Scientists have discovered a molecule that can interrupt an important stage in the development of Alzheimer's disease. The molecule sticks to faulty proteins and stops them forming toxic clusters in the brain.

The chaperone molecules - black dots - bind to the amyloid fibril.

Image credit: S. Cohen

The UK and Swedish researchers suggest their finding will help the discovery of drugs that could halt Alzheimer's disease progression.

They write about their discovery and its implications in the journal Nature Structural & Molecular Biology.

Lead author Dr. Samuel Cohen - a research fellow at St John's College in Cambridge, UK - says with studies like theirs, we are beginning to reap the rewards of the extensive work that has been done to increase our understanding of the microscopic processes involved in the development of Alzheimer's. He adds:

"Our study shows, for the first time, one of these critical processes being specifically inhibited, and reveals that by doing so we can prevent the toxic effects of protein aggregation that are associated with this terrible condition."

Many functions in cells are carried out by carefully folded proteins. Folding is an energy-efficient way of ensuring distant parts of the protein molecule that need to interact are near each other. Some of these structures are complex and need the help of housekeeping molecules called "chaperones."

A key step in the development of Alzheimer's and other degenerative diseases is the accumulation or "nucleation" of misfolded proteins - known as amyloid fibrils - that do not disperse or dissolve away but form toxic clusters and help the disease spread in the brain.

The molecule that the international team has discovered is a chaperone called Brichos that sticks to threads of amyloid fibrils and stops them coming into contact with each other, thus breaking the toxic chain reaction.

Brichos interrupts chain reaction that speeds up progression of Alzheimer's

Previous work by this team and others suggest there is a another critical step in the development of Alzheimer's disease. As amyloid fibrils begin to form, they cause other proteins to misfold and form small clusters called oligomers. These are highly toxic to nerve cells and are thought to be responsible for the devastating effect of Alzheimer's disease.

This second stage - called secondary nucleation - is what scientists believe sets off the chain reaction that speeds up the progression of Alzheimer's. Without secondary nucleation, single molecules would have to misfold and form clusters without help - a much slower and less devastating process.

Thanks to the huge amount of work that has gone on in this field, the team has collected a wealth of data so they can model what happens not only as Alzheimer's progresses, but also what happens if a step is interrupted or switched off.

The study shows that Brichos effectively blocks secondary nucleation and stops the chain reaction that speeds up Alzheimer's disease.

In humans, Brichos helps proteins avoid misfolding. Lab tests showed that when the chaperone encounters an amyloid fibril, it binds itself to sites on its surface forming a coating that stops it helping other proteins to misfold and nucleate into toxic oligomers.

Tests in living mice confirmed that the molecule suppressed the chain reaction from secondary nucleation.

Dr. Cohen says it may not be difficult to find other molecules that do this; until recently, it had just been unclear what to look for. He notes:

A good tactic now is to search for other molecules that have this same highly targeted effect and to see if these can be used as the starting point for developing a future therapy."

Last month, Medical-Diag.com learned of a study that found a significant link between high use of anticholinergic drugs and increased risk of developing dementia and Alzheimer's disease in older people. Anticholinergic drugs include many popular non-prescription sleep aids and the antihistamine Benadryl (diphenhydramine).

One STEP Closer to Curing Alzheimer's Disease. Animation by The Art of the Cell (Video Medical And Professional 2020).

Section Issues On Medicine: Disease