Scientists at the University of California, Los Angeles, used a molecule found in green tea to identify additional molecules that can break up protein tangles in the brain that are thought to cause Alzheimer’s and similar diseases.
The green tea molecule, EGCG, is known to break down tau fibers -; Long, multi-layered filaments form tangles that attack neurons, leading to their death.
In a paper published in Nature Communications, UCLA biochemists describe how EGCG captures tau fibers layer by layer. They also showed how they discovered other molecules that likely act in the same way that would make potential candidates better than EGCG, which cannot easily penetrate the brain. This discovery opens new possibilities for combating Alzheimer’s disease, Parkinson’s disease and related diseases through the development of drugs that target the structure of tau and other amyloid fibrils.
Thousands of layers of J-shaped tau molecules linked together form a type of amyloid fiber known as a tangle, which was first observed by Alois Alzheimer’s a century ago in the postmortem brain of a dementia patient. These fibers grow and spread throughout the brain, killing neurons and atrophying the brain. Many scientists believe that removing or destroying tau fibers can stop the progression of dementia.
“If we can untangle these fibers, we may be able to stop the death of neurons,” said David Eisenberg, a UCLA professor of chemistry and biochemistry, whose lab led the new research. “The industry has generally failed to do this because it has primarily used large, hard-to-reach antibodies in the brain. For two decades, scientists have known that there is a molecule in green tea called EGCG that can break down amyloid fibres, and that’s where we’re working away from the rest”.
EGCG has been extensively studied but has never worked as a drug for Alzheimer’s because its ability to break down tau fibers works best in water, and does not easily enter cells or the brain. Also, once EGCG enters the bloodstream, it binds to many proteins along with the tau fibers, impairing its effectiveness.
To investigate the mechanisms by which EGCG breaks down tau fibers, researchers extracted tau synapses from the brains of people who had died of Alzheimer’s disease and incubated them for varying periods of time with EGCG. Within three hours, half of the fibers were gone and those that remained were partially degraded. After 24 hours, all fibers were gone.
The fibers were frozen in the intermediate stage of EGCG-induced decomposition, and images of these frozen samples showed how EGCG cut the fibers into seemingly harmless pieces.
The EGCG molecules bind to each layer of the fiber, but the molecules want to be closer together. As they move together, the fibers burst. “
David Eisenberg, Professor of Chemistry and Biochemistry at UCLA
Kevin Murray, who was a UCSD doctoral student at the time and now in Brown University’s Department of Neurology, identified specific sites, called drug carriers, on the tau fibers to which EGCG molecules bind. Then he ran computer simulations on a library of 60,000 small molecules that are friendly to the nervous system and the brain, with the ability to bind to the same sites. He has found several hundred molecules with a size of 25 atoms or less, all of which have the ability to bind better with drug packages than tau fibers. Experiments with the best candidate molecules identified from the computational examination identified about half a dozen molecules that broke down tau fibers.
“Using the supercomputing resources available at the University of California, Los Angeles, we can screen huge libraries of drugs virtually before any wet lab experiments are needed,” Murray said.
A few of these higher compounds, most notably molecules called CNS-11 and CNS-17, also stopped the fibers from spreading from one cell to another. The authors believe that these molecules are candidates for drugs that could be developed to treat Alzheimer’s disease.
“For cancer and many metabolic diseases, knowing the structure of the disease-causing protein has led to effective drugs that stop the disease-causing action,” Eisenberg said. “But only recently have scientists learned the structures of tau tangles. We have now identified the small molecules that break up these fibers. To sum up, we’ve put Alzheimer’s and amyloid diseases in general on the same foundation as cancer, that is, this structure can be used to find drugs.”
CNS-11 is not yet a drug, but the authors call it a pioneer.
“By studying different forms of this, which is what we do, we might move from this to something that’s going to be really good medicine,” Eisenberg said.
The paper, “Structure-based discovery of small molecules separating Alzheimer’s tissue-derived tau fibers in vitro,” was funded primarily by the Institute on Aging of the National Institutes of Health, and the Howard Hughes Medical Institute.