Green tea molecule can break protein tangles in the brain that cause Alzheimer’s disease

Scientists at UCLA have used a molecule found in green tea to identify additional molecules that could break protein tangles in the brain thought to cause Alzheimer’s and similar diseases.

The green tea molecule, EGCG, is known to break down tau fiber -; long, multilayered filaments that form tangles that attack neurons, causing them to die.

In a paper published in nature communication, UCLA biochemists describe how EGCG snaps together tau fibers layer by layer. They also show how they discovered other molecules that would likely act similarly and be better potential drug candidates than EGCG, which cannot easily enter the brain. The finding opens up new possibilities for fighting Alzheimer’s, Parkinson’s and related diseases by developing drugs that target the structure of tau fibers and other amyloid fibrils.

Thousands of J-shaped layers of tau molecules bound together form the type of amyloid fibrils known as tangles, first observed a century ago by Alois Alzheimer in the postmortem brain of a patient with dementia. These fibers grow and spread throughout the brain, killing neurons and causing brain atrophy. Many scientists believe that removing or destroying tau fibers can halt the progression of dementia.

“If we could break these fibers, maybe we could stop the death of neurons,” said David Eisenberg, a professor of chemistry and biochemistry at UCLA whose lab led the new research. “The industry has generally failed to do this because they mainly used large antibodies that are difficult to get into the brain. Scientists have known for a few decades that there is a molecule in green tea called EGCG that can break down amyloid fibers, and That’s where our work differs from the rest.”

EGCG has been studied extensively but has never worked as a drug for Alzheimer’s disease because its ability to dismantle tau fibers works best in water and it doesn’t easily enter cells or the brain. Once EGCG enters the bloodstream, it also binds to many proteins in addition to tau fibers, weakening its effectiveness.

To investigate the mechanisms by which EGCG breaks down tau fibres, the researchers extracted tau tangles from the brains of people who died of Alzheimer’s disease and incubated them with EGCG for varying lengths of time. Within three hours, half of the fibers had disappeared and the remaining fibers had partially broken down. After 24 hours all fibers had disappeared.

Fibrils in the middle stage of EGCG-induced degradation were rapidly frozen and images of these frozen samples showed how EGCG broke the fibrils into seemingly harmless pieces.

The EGCG molecules bind to each layer of the fibers, but the molecules want to be closer together. As they move toward each other, the fiber snaps.”


David Eisenberg, UCLA Professor of Chemistry and Biochemistry

Kevin Murray, who was a UCLA doctoral student at the time and now in the neurology department at Brown University, identified specific locations, called pharmacophores, on the tau fiber to which EGCG molecules were attached. He then ran computer simulations on a library of 60,000 brain and nervous system-friendly small molecules with the potential to bind to the same sites. He found several hundred molecules that were 25 atoms or less in size, all with the potential to bind even better to the tau fiber pharmacophores. Experiments on the key candidate molecules identified from the computational screening identified about half a dozen breaking the tau fibers.

“Using the supercomputing resources available at UCLA, we are able to virtually screen huge libraries of drugs before the need for wet lab experiments,” Murray said.

A few of these top compounds, specifically molecules called CNS-11 and CNS-17, also kept the fibers from spreading from cell to cell. The authors think 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 it’s only recently that scientists have learned the structures of tau tangles. We’ve now identified small molecules that break down these fibers. Basically, we’ve put Alzheimer’s disease and amyloid disease in general on the same footing as cancer, namely, that structure can be used to find drugs.”

CNS-11 isn’t a drug yet, but the authors call it a clue.

“By studying variations of this, which we’re doing, we can go from this lead to something that would be really good medicine,” Eisenberg said.

The article, “Structure-based discovery of small molecules that disaggregate in vitro tissue-derived tau fibrils of Alzheimer’s disease,” was funded primarily by the National Institutes of Health’s Institute of Aging and the Howard Hughes Medical Institute.

Source:

University of California – Los Angeles

Reference magazine:

Seidler, PM, et al. (2022) Structure-based discovery of small molecules that disaggregate Alzheimer’s disease-derived tau fibrils in vitro. Nature Communication. doi.org/10.1038/s41467-022-32951-4.

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