UCLA researchers have employed a chemical from green tea to find more compounds that might disassemble protein tangles in the brain thought to be the root cause of Alzheimer's and related disorders.
UCLA biochemists detail how EGCG breaks tau fibres layer by layer in a report that was published in Nature Communications. They also describe how they found additional compounds that are likely to function in the same manner and might be used as medications rather than EGCG, which is difficult to enter the brain.
In order to find new molecules that could disassemble the protein tangles in the brain thought to be the origin of Alzheimer’s and related disorders, UCLA researchers employed a chemical found in green tea. Tau fibres, which are lengthy, multilayered filaments that create tangles and target neurons, are known to be destroyed by the green tea ingredient EGCG.
“If we could break up these fibers we may be able to stop death of neurons,” said David Eisenberg, UCLA professor of chemistry and biochemistry whose lab led the new research. “Industry has generally failed at doing this because they mainly used large antibodies that have difficulty getting into the brain. For a couple of decades, scientists have known there’s a molecule in green tea called EGCG that can break up amyloid fibers, and that’s where our work departs from the rest.”
The form of amyloid fibrils known as tangles, first discovered in the post-mortem brain of a dementia patient a century ago by Alois Alzheimer, are made up of thousands of J-shaped layers of tau molecules joined together. As these fibres proliferate and travel throughout the brain, they suffocate neurons and cause atrophy. Many researchers believe that tau fibres can be removed or destroyed in order to slow the course of dementia.
The ability of EGCG to break down tau fibres works best in water and it is difficult for it to reach cells or the brain, therefore despite significant research, it has never proven effective as a treatment for Alzheimer’s. Additionally, EGCG loses its effectiveness as soon as it reaches the bloodstream because it binds to proteins other than tau fibres.
The scientists took tau tangles from the brains of persons who had died of Alzheimer’s and incubated them with EGCG for varied lengths of time to examine the processes by which EGCG breaks up tau fibres. The remaining fibres were partially damaged and half of them were gone within three hours. All of the fibres had vanished after 24 hours.
Images of flash-frozen fibrils at the middle stage of EGCG-induced breakdown demonstrated how the compound broke the fibrils into seemingly unharmful fragments.
“For cancer and many metabolic diseases knowing the structure of the disease-causing protein has led to effective drugs that halt the disease-causing action,” Eisenberg said. “But it’s only recently that scientists learned the structures of tau tangles. We’ve now identified small molecules that break up these fibers. The bottom line is, we’ve put Alzheimer’s disease and amyloid diseases in general on same basis as cancer, namely, that structure can be used to find drugs.””By studying variations of this, which we are doing, we may go from this lead into something that would be a really good drug,” Eisenberg said.
The particular places, known as pharmacophores, on the tau fibre that EGCG molecules adhered to were found by Kevin Murray, a neurology professor at Brown University who was a doctorate student at UCLA at the time. Then he used computer simulations to test 60,000 tiny compounds that were friendly to the nervous system and the brain and had the ability to bind to the same locations.
“Using the super-computing resources available at UCLA, we are able to screen vast libraries of drugs virtually before any wet-lab experiments are required,” Murray said.
He discovered several hundred compounds with 25 or fewer atoms, all of which had the capacity to bind the tau fibre pharmacophores even more effectively. About a half-dozen compounds from the top candidate molecules discovered through the computer screening were found through experiments to disrupt the tau fibres.
Several of these potent substances, most notably the molecules CNS-11 and CNS-17, also prevented the fibres from migrating from one cell to another. These compounds, according to the authors, are potential candidates for medications being created to treat Alzheimer’s disease.
Although CNS-11 is not yet a medicine, the authors refer to it as a lead.