Study Title:

Green Tea Inhibits Amyloid Plaque Formation

Study Abstract

Despite the significance of Alzheimer’s disease, the link between metal-associated amyloid-β (metal–Aβ) and disease etiology remains unclear. To elucidate this relationship, chemical tools capable of specifically targeting and modulating metal–Aβ species are necessary, along with a fundamental understanding of their mechanism at the molecular level. Herein, we investigated and compared the interactions and reactivities of the green tea extract, (−)-epigallocatechin-3-gallate [(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5-trihydroxybenzoate; EGCG], with metal [Cu(II) and Zn(II)]–Aβ and metal-free Aβ species. We found that EGCG interacted with metal–Aβ species and formed small, unstructured Aβ aggregates more noticeably than in metal-free conditions in vitro. In addition, upon incubation with EGCG, the toxicity presented by metal-free Aβ and metal–Aβ was mitigated in living cells. To understand this reactivity at the molecular level, structural insights were obtained by ion mobility-mass spectrometry (IM-MS), 2D NMR spectroscopy, and computational methods. These studies indicated that (i) EGCG was bound to Aβ monomers and dimers, generating more compact peptide conformations than those from EGCG-untreated Aβ species; and (ii) ternary EGCG–metal–Aβ complexes were produced. Thus, we demonstrate the distinct antiamyloidogenic reactivity of EGCG toward metal–Aβ species with a structure-based mechanism.

From press release:

Researchers at the University of Michigan have found a new potential benefit of a molecule in green tea: preventing the misfolding of specific proteins in the brain.

The aggregation of these proteins, called metal-associated amyloids, is associated with Alzheimer's disease and other neurodegenerative conditions.

A paper published recently in the Proceedings of the National Academy of Sciences explained how U-M Life Sciences Institute faculty member Mi Hee Lim and an interdisciplinary team of researchers used green tea extract to control the generation of metal-associated amyloid-β aggregates associated with Alzheimer's disease in the lab.

The specific molecule in green tea, ( -- )-epigallocatechin-3-gallate, also known as EGCG, prevented aggregate formation and broke down existing aggregate structures in the proteins that contained metals -- specifically copper, iron and zinc.

"A lot of people are very excited about this molecule," said Lim, noting that the EGCG and other flavonoids in natural products have long been established as powerful antioxidants. "We used a multidisciplinary approach. This is the first example of structure-centric, multidisciplinary investigations by three principal investigators with three different areas of expertise."

The research team included chemists, biochemists and biophysicists.

While many researchers are investigating small molecules and metal-associated amyloids, most are looking from a limited perspective, said Lim, assistant professor of chemistry and research assistant professor at the Life Sciences Institute, where her lab is located and her research is conducted.

"But we believe you have to have a lot of approaches working together, because the brain is very complex," she said.

The PNAS paper was a starting point, Lim said, and her team's next step is to "tweak" the molecule and then test its ability to interfere with plaque formation in fruit flies.

"We want to modify them for the brain, specifically to interfere with the plaques associated with Alzheimer's," she said.

Lim plans to collaborate with Bing Ye, a neurobiologist in the LSI. Together, the researchers will test the new molecule's power to inhibit potential toxicity of aggregates containing proteins and metals in fruit flies.

Study Information

S.-J. Hyung, A. S. DeToma, J. R. Brender, S. Lee, S. Vivekanandan, A. Kochi, J.-S. Choi, A. Ramamoorthy, B. T. Ruotolo, M. H. Lim.
Insights into antiamyloidogenic properties of the green tea extract (-)-epigallocatechin-3-gallate toward metal-associated amyloid- species
Proceedings of the National Academy of Sciences
2013 March
Life Sciences Institute, University of Michigan, Ann Arbor, MI.

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