The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 7 No.
4 • September 2004
Disaggregating Toxic Protein Clumps in Neurodegenerative and other Chronic Diseases: Dopamine, L-Dopa, and Adrenaline
Last issue, we discussed (see
“Connecting Alzheimer’s, Cardiovascular Disease, Parkinson’s Disease, and Type 2 Diabetes”) some of the aggregated proteins involved in the title diseases and possible ways to get rid of some of them. A great deal of further work on how to prevent abnormal protein clumps from forming and how to get rid of clumps once they have formed has been published. Here are some of the latest.
One recent paper shows that catecholamines [dopamine, L-dopa, adrenaline (also called epinephrine)] inhibit fibrillation of amyloid-beta (as found in Alzheimer’s) and alpha-synuclein (Parkinson’s disease). More interestingly, the researchers found that oxidized metabolites (such as quinones and aminochromes) of these catecholamines were actually more effective in inhibiting fibrillation than the parent catecholamines themselves. Dopamineochrome and adrenochrome were specifically shown to inhibit alpha-synuclein fibrillation. The researchers found that coincubation of ascorbic acid or soluble vitamin E with these compounds had no effect on dopamine or L-dopa inhibition of fibrillation, though they reported that ascorbic acid itself caused weak inhibition of fibrillation.
Not only did the catecholamines inhibit fibrillation, but they also caused disaggregation of existing fibrils. These results suggest that increasing the supplies of catecholamine precursors, such as tyrosine and phenylalanine (along with their cofactors vitamins C and B6, folic acid, and copper) may be a useful strategy in helping to reduce the formation of, as well as disaggregating, amyloid-beta and alpha-synuclein fibrils.
The authors note, “Our data indicate that the presence of micromolar concentrations of dopamine or L-dopa is sufficient to significantly inhibit fibril formation or disaggregate existing fibrils of amyloid-beta or alpha-synuclein in vitro. Because estimates of dopamine concentrations in striatal-nerve terminals and L-dopa concentrations in the striatum after administration are >>50 and 50 µM, respectively, the concentrations used in our experiments are physiologically relevant.”
Red Wine Polyphenols
A study of the effects of several red wine-related polyphenols on the formation of amyloid-beta fibrils in vitro reports that several of them dose-dependently inhibited the formation of fibrillated amyloid-beta, with the activity decreasing in order of myricetin = morin = quercetin > kaempferol > (+)-catechin = (-)-epicatechin. The polyphenols were also reported to destabilize preformed fibrillated amyloid-beta protein. For example, they found that when fresh amyloid-beta(1–40) was incubated with fibrillated amyloid beta(1–40), there was clear fibril extension, as observed under electron microscopy. However 50-µM myricetin completely abolished the extension. Myricetin also abolished the extension of fibrillated amyloid-beta(1–42), while morin, quercetin, and kaempferol inhibited the extension of both these fibrillated amyloid-beta forms.
The authors propose that their results may help explain the negative correlation between moderate red wine drinking and the occurrence of Alzheimer’s disease.
- Li et al. Dopamine and L-dopa disaggregate amyloid fibrils: implications for Parkinson’s and Alzheimer’s disease. FASEB J 2004 Jun;18(9):962-4. See also Epub 2004 Apr 1.
- Ono et al. Potent anti-amyloidogenic and fibril-destabilizing effects of polyphenols in vitro: implications for the prevention and therapeutics of Alzheimer’s disease. J Neurochem 87:172-81 (2003).