Natural Products Detoxify Amyloid Oligomers and May Prevent Alzheimer's Disease

Molecular biologists studying the mechanisms that lead to the development of Alzheimer's disease have found that the process requires binding of amyloid-beta (A-beta) oligomers to neuron membrane prion protein (PrPC), a process that can be blocked by the natural compounds resveratrol and epigallocatechin gallate (EGCG).

Resveratrol is found primarily in the skin and seeds of grapes. The amount found in grape skins varies with the grape cultivar, its geographic origin, and exposure to fungal infection. The amount of fermentation time a wine spends in contact with grape skins is an important determinant of its resveratrol content. Epidemiological and experimental reports have linked mild-to-moderate wine and/or grape consumption to a lowered risk of cardiovascular, cerebrovascular, and peripheral vascular diseases. EGCG is the most abundant catechin in tea and is a potent antioxidant that may have therapeutic applications in the treatment of many disorders. It is found in green tea but not black tea.

Investigators at the University of Leeds (United Kingdom) worked with an in vitro model of Alzheimer's disease. They used fluorescence microscopy to study the binding of A-beta oligomers to brain cells and examined the effect of exposure to resveratrol and EGCG on the binding process.

They reported in the February 5, 2013, online edition of the Journal of Biological Chemistry that A-beta oligomers bound preferentially to cells and neurons expressing PrPC. Binding of A-beta oligomers to cell surface PrPC was dependent on the integrity of cholesterol-rich lipid rafts. Lipid rafts are highly organized microdomains within the plasma membrane of cells, which are composed of a combination of glycosphingolipids and protein receptors. These specialized membrane microdomains compartmentalize cellular processes by serving as organizing centers for the assembly of signaling molecules, influencing membrane fluidity and membrane protein trafficking, and regulating neurotransmission and receptor trafficking. Lipid rafts are more ordered and tightly packed than the surrounding membrane, but float freely in the membrane bilayer.

Binding of A-beta oligomers to PrPC was inhibited by changes in the shape of the oligomers induced by exposure to either resveratrol or EGCG. A-beta oligomers that had been reshaped by these compounds failed to bind to PrPC and were no longer toxic to nerve cells.

"This is an important step in increasing our understanding of the cause and progression of Alzheimer's disease," said senior author Dr. Nigel Hooper professor of biochemistry at the University of Leeds. "It is a misconception that Alzheimer's is a natural part of ageing; it is a disease that we believe can ultimately be cured through finding new opportunities for drug targets like this."

The investigators formed amyloid balls in a test tube and added them to human and animal brain cells. Prof. Hooper said, "When we added the extracts from red wine and green tea, which recent research has shown to reshape amyloid proteins, the amyloid balls no longer harmed the nerve cells. We saw that this was because their shape was distorted, so they could no longer bind to prion and disrupt cell function. We also showed, for the first time, that when amyloid balls stick to prion, it triggers the production of even more amyloid, in a deadly vicious cycle. I am certain that this will increase our understanding of Alzheimer's disease even further, with the potential to reveal yet more drug targets."

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University of Leeds