New Molecule Destroys Alzheimer’s-Causing Amyloid Tangles

A molecule found in green tea helped UCLA biochemists in the discovery of multiple molecules capable of destroying tau fibers.

University of California, Los Angeles (UCLA) researchers used a molecule present in green tea to uncover more molecules that may break up protein tangles in the brain, which are known to cause Alzheimer’s disease and other disorders.

Tau fibers, which are lengthy, multilayered filaments that create tangles and attack neurons, are known to be broken up by the green tea molecule EGCG.

Advertisement

UCLA biochemists detail how EGCG breaks tau fibers layer by layer in a paper that was recently published in the journal Nature Communications. They also describe how they found other compounds that are likely to function in the same manner and might be better potential candidates for drugs than EGCG, which has difficulty penetrating the brain. The discovery offers up new possibilities for treating Alzheimer’s, Parkinson’s, and other neurodegenerative diseases by developing drugs that target the structure of tau fibers and other amyloid fibrils.

Thousands of J-shaped layers of tau molecules joined together form the type of amyloid fibrils known as tangles, which were originally identified in the post-mortem brain of a dementia patient by Alois Alzheimer a century ago. As these fibers grow and spread throughout the brain, they kill neurons and cause brain atrophy. Many researchers believe that the removal or destruction of tau fibers can slow the progression of dementia.

“If we could break up these fibers we may be able to stop the 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.”

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

To investigate the mechanisms through which EGCG breaks up tau fibers, the researchers extracted tau tangles from the brains of people who died from Alzheimer’s and incubated them for varying amounts of time with EGCG. Within three hours, half the fibers were gone and those that remained were partially degraded. After 24 hours, all the fibers had disappeared.

Fibrils in the middle stage of EGCG-induced degradation were flash-frozen, and images of these frozen samples showed how EGCG snapped the fibrils into apparently harmless pieces.

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

Kevin Murray, who was a UCLA doctoral student at the time and is now in the neurology department at Brown University, identified specific locations, called pharmacophores, on the tau fiber to which EGCG molecules are attached. Then he 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 with the top candidate molecules identified from the computational screening identified about a half dozen that broke up the tau fibers.

“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.

A few of these top compounds, most notably molecules called CNS-11 and CNS-17, also stopped 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 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 the same basis as cancer, namely, that structure can be used to find drugs.”

CNS-11 is not a drug yet but the authors call it a lead.

“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.

Reference: “Structure-based discovery of small molecules that disaggregate Alzheimer’s disease tissue derived tau fibrils in vitro” by Paul M. Seidler, Kevin A. Murray, David R. Boyer, Peng Ge, Michael R. Sawaya, Carolyn J. Hu, Xinyi Cheng, Romany Abskharon, Hope Pan, Michael A. DeTure, Christopher K. Williams, Dennis W. Dickson, Harry V. Vinters and David S. Eisenberg, 16 September 2022, Nature Communications.
DOI: 10.1038/s41467-022-32951-4

The study was funded by the National Institutes of Health’s Institute of Aging and the Howard Hughes Medical Institute.