Writing in Nature, Israeli researchers identify the polyphenols epigallocatechin gallate (EGCG) and tannic acid (TA) found in green tea and red wine respectively.
These compounds appear to help prevent the toxic amyloid structures from building up in the brain that go on to cause neurodegeneration, in a series of mechanisms confirmed by computer models.
“Our new study demonstrates once again the ability of nature to produce the best candidate of drugs to treat some of the worst human maladies," said study author Shira Shaham-Niv, who is based at the department of molecular microbiology and biotechnology at Tel Aviv University.
"In our new study, we examined whether the molecules identified in past studies on Alzheimer's disease and other amyloid diseases, which are known to inhibit the formation of amyloid aggregates, could also help counteract the amyloid formation process of metabolites in metabolic diseases."
Although a number of approaches exist to reduce the production of amyloid deposits, the use of polyphenols show particular promise due to their ability to interfere with amyloid assembly at the molecular level.
High concentrations of polyphenols are naturally found in plants, where they work to protect against diseases and UV light. These molecules have also demonstrated inhibition of amyloid self-assembly in vitro.
Moreover, dietary polyphenols have shown beneficial health-promoting effects in chronic and neurodegenerative diseases.
Led by professor Ehud Gazit from Tel Aviv University’s faculty of life science, the team used culture cell systems and in vitro techniques to test EGCG and TA.
These compounds were tested on three amyloid protein-like metabolites related to three metabolic diseases: adenine, cumulative tyrosine and phenylalanine. One other compound, acetylsalicylic acid was used as a control.
The results were promising with the compounds appearing to reduce the cytotoxicity triggered by these metabolite structures. In contrast, acetylsalicylic acid did not have an inhibitory effect.
Computer simulations were used to verify the mechanism of action driving these compounds.
“We demonstrated that in spite of the generic inhibition, the compounds function via two different mechanisms,” the researchers said.
“Although EGCG affects both early and later stages of fibrillation, TA is only effective in the early state.”
Amyloid binding strength
The simulation also served to provide molecular details about the nature of the binding of the two inhibitors, EGCG and TA to the studied metabolites.
“It appears that each metabolite binds to both inhibitors with similar energy. At the molarity experimentally used here, the two inhibitors also bind a comparable number of free metabolites,” the study observed.
“However, at this molarity, the number of EGCG molecules binding to the crystalline form is several fold higher than the TA molecules, providing a theoretical framework to understand the distinct effect of the inhibitors when added at different stages of amyloid self-assembly.”
The findings here build on previous studies by the same team and others in which phenylalanine was shown to be capable of self-assembly and of forming amyloid structures like those seen in Alzheimer's, Parkinson's and other neurodegenerative diseases.
In the second study, other metabolites that accumulate in other inborn congenital metabolic diseases were also shown to undergo self-assembly processes and form toxic amyloid aggregates.
Source: Nature Communications Chemistry
Published online ahead of print: DOI: 10.1038/s42004-018-0025-z
“Differential inhibition of metabolite amyloid formation by generic fibrillation-modifying polyphenols.”
Authors: Shira Shaham-Niv, Pavel Rehak, Dor Zaguri, Aviad Levin, Lihi Adler-Abramovich, Lela Vuković, Petr Král, Ehud Gazit.