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.