Progress on treating Alzheimer’s disease has been frustratingly slow. A group of scientists suggest frustration at a very small scale may lead to a new path toward treatment.

Researchers found through experiments and computations 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.

Folding proteins tend to look for the easiest way to get to their functional forms. Similarly, amyloid beta peptides look for the easiest way to bind to the tips of growing fibrils, but are sometimes held back -- or frustrated -- when the positive and negative forces between atoms don’t immediately align.

When they do finally align, the growing fibrils form the gummy plaques implicated in Alzheimer’s and other neurological diseases. New research in the Proceedings of the National Academy of Sciences shows that drugs might be developed to take advantage of the peptides’ frustrated intermediate states to stabilize the fibril tips and block further aggregation.  

The senior author, said it wasn’t a stretch to look at amyloid beta fibril growth in his lab. “Previous studies that observed fibrilizing proteins with an atomic force microscope focused on more exotic behaviors because amyloid beta fibrils with a steady rate of growth are kind of boring,” the author said. 

“But I was fascinated because the correlation of the growth rate to the concentration of peptides in the solution carries loads of information,” the senior author said. “It helps to measure the rate constant, a quantity which is easy to model.”

The authors suggested that disrupting the steady growth with urea, known to denature (or unfold) proteins, might provide useful data about how amyloid fibrils form. It sure did. 

“A weird thing happened,” the author said. “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,” the author said. “We thought, this is trying to tell us something.”

Further experiments showed that urea “destabilized the wrong peptide bonds,” the author  said. “It made the fibril grow faster but also showed us the intermediate frustrated steps. The big thing is we now have evidence that at the end of the fibril there’s a crown of frustrated, disordered peptide chains trying to dock and lock, and these are druggable targets. 

“It’s irrational to block every single peptide, because there are probably 100,000 times more of them than there are fibril tips,” the author said. “The beauty of what we found is that the fibril tip is an Achilles’ heel of fibrilization, and all we have to do is block the complex at the tip.”

 “Two things have emerged from the experiments,” another author said. “One is that almost all of the kinetic models people use for amyloid beta growth are too simple. That’s not unexpected. The other is that denaturing changes the equilibrium, and it can also change the rate of folding in in ways that tell you where the transitions states appear. 

“In the earlier paper on fibril nucleation, we remarked that it looked like there were some strange processes where the proteins had to backtrack from the transition state,” the co- author said.

The author said having a way to halt fibrils from growing 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,” the author added. “This, of course, gets into the big argument over whether fibrils are good or bad.”

Computational models might show that arresting the fibrils could either stem the effects of Alzheimer’s or make it worse. Either way, the author said scientists will have a more definitive answer.

“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,” the author said. “Either way, those molecules will provide interesting tools to understand how fibril growth happens.”

https://news.rice.edu/2021/09/13/docking-peptides-slow-to-lock-open-possible-path-to-treat-alzheimers/

https://www.pnas.org/content/118/38/e2110995118