Novel Treatment Strategies of Alzheimer’s Disease

Alzheimer’s disease (AD) and exploring its treatment strategies have been frustratingly slow. Amongst these lags, scientists at the University of Houston (UH) and Rice University suggest a new path towards AD treatment, as published in the Proceedings of the National Academy of Sciences. Alzheimer's disease (AD) is a neurodegenerative disease that leads to gradual memory loss and behavioral changes. It is characterized by the formation of beta-amyloid plaques in the brain tissues, years before the actual symptoms occur.

The study carried out experiments and computations to find that amyloid-beta peptides, small molecules that are abundant in the brain, go through several intermediate stages of frustration as they “dock and lock” to the tips of growing fibrils.

Amyloid beta peptides functionally look for the easiest way to bind to the tips of growing fibrils. However certain positive and negative forces between atoms don’t immediately align and result in setback or frustration of these peptides.

After the setback, the resulting alignment constitutes the growing fibrils to form the gummy plaques implicated in Alzheimer’s and other neurological diseases. Present study hit the jackpot by suggesting that these frustrated intermediate states of the peptides can be utilized to stabilize the fibril tips and block further aggregation through drugs.

Amyloid Proteins and Drugs Targets

Moreover disrupting the steady growth of these proteins with urea (known to denature (or unfold) proteins) provided useful data about how amyloid fibrils form.

“A weird thing happened. Urea made the fibrils less stable, which meant the bonds between the molecules in the fibrils became less strong. But it also made them grow faster. This is a very serious contradiction, a violation of the empirical rules of chemistry. But there are empirical rules, and then there are fundamental laws. We thought, this is trying to tell us something, ” says UH chemical and biomolecular engineer Peter Vekilov.

The team conducted further experiments that showed that urea destabilized the wrong peptide bonds. Although urea made the fibril grow faster, it also revealed the intermediate frustrating steps.

This contributed to breakthrough data on the presence of crowns of frustrated, disordered peptide chains at the end of the fibril that is trying to dock and lock. These form a great target for drugs.

Moreover, these findings may help settle a long-standing disagreement among scientists over whether fibrils cause neurological disease or protect the brain from another suspect, particularly tangled tau proteins.

“Our idea is to poison the tip so that it can’t grow, rather than to destabilize the whole fibril. This, of course, gets into the big argument over whether fibrils are good or bad. To my mind, what’s interesting here is to provide a new target, and we will explore some possible drugs that could change the nature of the tip. Either way, those molecules will provide interesting tools to understand how fibril growth happens,” says Rice physicist Peter Wolynes.

Source-Medindia