Abstract
Deposition of Aβ42 aggregates in the form of amyloid plaques is a pathological hallmark of Alzheimer’s disease. A desired avenue of intervention is the inhibition of Aβ42 aggregation. Epigallocatechin gallate (EGCG), the main polyphenol in green tea, has been generally considered an inhibitor of Aβ aggregation. However, previous experiments focused on the reduction of the amount of Aβ42 aggregates, while the effect of EGCG on the rate of Aβ42 aggregation was not critically analyzed. Here we performed an experimental evaluation of Aβ42 aggregation kinetics in the absence and presence of EGCG at a wide range of concentrations. We found that EGCG reduced thioflavin T fluorescence in an EGCG concentration-dependent manner, suggesting that EGCG reduced the amount of Aβ42 fibrils. The effect of EGCG on the rate of Aβ42 aggregation appears to be bimodal. We found that higher EGCG-to-Aβ42 ratios promoted the rate of Aβ42 aggregation, while lower EGCG-to-Aβ42 ratios inhibited the aggregation rate. To confirm that the reduction of thioflavin T fluorescence is due to the lowered aggregate quantity, but not due to perturbation of thioflavin T binding to Aβ42 fibrils, we probed the effect of EGCG on Aβ42 aggregation using site-directed spin labeling. Electron paramagnetic resonance of spin-labeled Aβ42 aggregates suggests that high EGCG-to-Aβ42 ratios led to a greatly reduced amount of Aβ42 fibrils, and these aggregates adopt similar structures as the fibrils in the no-EGCG sample. Potential implications of this work in designing prevention or therapeutic strategies using EGCG are discussed.
Highlights
Alzheimer’s disease, the most common cause of dementia, has two pathological hallmarks: amyloid plaques and neurofibrillary tangles.[1−3] Amyloid plaques consist of the fibrillar aggregates of Aβ protein, while tau aggregates make up the neurofibrillary tangles
Aβ40 is the most abundant isoform of Aβ in the brain, several folds more than Aβ42, but Aβ42 is the major Aβ isoform in the plaques.[7−10] Formation of Aβ fibrils is a result of Aβ aggregation, a process that has been extensively studied.[11−17] With amyloid being the central player of the amyloid cascade hypothesis, inhibiting Aβ aggregation is an obvious avenue for therapeutic intervention
Using a recombinant system to produce Aβ proteins, we have demonstrated the capability to generate aggregation kinetics data with well-resolved lag phase.[37−39] This allows us to study the effect of Epigallocatechin gallate (EGCG) on the rate of Aβ42 aggregation
Summary
Alzheimer’s disease, the most common cause of dementia, has two pathological hallmarks: amyloid plaques and neurofibrillary tangles.[1−3] Amyloid plaques consist of the fibrillar aggregates of Aβ protein, while tau aggregates make up the neurofibrillary tangles. In addition to the rate of aggregation, EGCG showed a concentration-dependent effect on the amplitude of thioflavin T fluorescence (Figure 2A). Xue et al showed that Aβ42 fibril amount scales linearly with thioflavin T fluorescence for the same type of fibril at a fixed thioflavin T concentration.[36] With the assumption that EGCG does not change the fibril structure or interfere with thioflavin T binding to a great extent, we can conclude that EGCG reduces the yield of Aβ42 aggregation in a concentration-dependent manner Aggregation kinetics shows that EGCG at these ratios reduced the thioflavin T fluorescence to nearbackground levels (Supporting Information Figure S2). EGCG can remodel preformed Aβ42 fibrils.[32] This effect can reduce the rate of secondary nucleation, which is catalyzed by fibrillar aggregates.[50] Perhaps, more surprising is the increased aggregation rate at high EGCG-to-Aβ ratios (Figure 2).
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