UCLA researchers used a molecule present in green tea to discover more molecules that could break the protein tangles in the brain, which are known to cause Alzheimer's disease and other diseases. Tau fibers are lengthy multilayer filaments that create tangles and attack neurons and are known to be decomposed by green tea molecule EGCG.
UCLA biochemists detail how EGCG breaks down tau fiber layer by layer in a recent paper published in the journal Nature-Communication. They also describe how they discovered other compounds that might work in the same way and could become a better potential drug candidate than EGCG, which is difficult to penetrate the brain.
This discovery offers new possibilities for the treatment of Alzheimer's, Parkinson's, and other neurodegenerative diseases, namely through the development of drugs targeting tau fibers and other amyloid fiber structures.
Thousands of J-shaped Dow molecules are connected together to form an amyloid fiber called tangles, which was originally discovered by Alois Alzheimer in the post-mortem brain of a dementia patient. As these fibers grow and spread throughout the brain, they kill neurons and cause brain atrophy. Many researchers believe that removing or destroying tau fibers can slow the progression of dementia. "If we can break these fibers, we might be able to stop the death of neurons," said David Eisenberg, a professor of chemistry and biochemistry at UCLA, and his lab led the new study. The industry often fails in this regard because they mainly use large antibodies that are difficult to get into the brain. For decades, scientists have known that there is a molecule in green tea called EGCG that breaks down amyloid fibers, which is how our work differs from others."
EGCG has been widely studied but has never worked as a drug to treat Alzheimer's because its ability to break down tau fibers works best in water, and it doesn't easily get into cells or brains." Furthermore, once EGCG enters the bloodstream, it binds to many proteins other than tau fibers, weakening its efficacy.
To study the mechanism by which EGCG breaks down tau fibers, the researchers extracted tau tangles from the brains of people who died of Alzheimer's disease and cultured them for different times from EGCG. Within three hours, half of the fibers disappeared and the remaining fibers were partially degraded. After 24 hours, all the fibers disappeared.
Fibers in the intermediate stage of EGCG-induced degradation were frozen by lightning, and images of these frozen samples showed how EGCG broke the fibers into obviously harmless fragments.
"EGCG molecules bind to each layer of the fiber, but the molecules want to bond more closely. When they move together, the fibers break," Eisenberg said.
Kevin Murray, who was a doctoral student at UCLA at the time, is now working in the Department of Neurology at Brown University, and he identified a specific location on Dow fibers where EGCG molecules are attached, called pharmacological groups. He then performed a computer simulation of 60,000 brains and nervous system -friendly small molecule libraries that could be bound to the same location. He found hundreds of molecules with a size of 25 atoms or smaller, all of which could better bind to the pharmacological effects of tau fibers. The experiment was conducted with the top candidate molecules screened out by calculation and found that about half a dozen molecules could decompose tau fibers. "Utilizing the existing supercomputing resources at UCLA, we were able to screen out a large library of drugs before any wet lab experiments are needed," Murray said. Several of these top compounds, most notably molecules called CNS-11 and CNS-17, also prevented the spread of fibers from cells. The authors believe that these molecules are drug candidates that can be developed to treat Alzheimer's disease.
Eisenberg said: "For cancer and many metabolic diseases, understanding the structure of pathogenic proteins has led to effective drugs that can stop pathogenic effects.But until recently, scientists learned about the structure of tau tangles. We have now identified small molecules that can break these fibers. The bottom line is that we have put Alzheimer's disease and amyloid disease in general on the same basis as cancer, i.e. structures can be used to find drugs. "
CNS-11 is not a drug yet, but the authors call it a clue. "By studying the changes in this, we are doing what we might go from this clue to a really good drug," Eisenberg said. "
