Can Activation of Acetylcholinesterase by β-Amyloid Peptide Decrease the Effectiveness of Cholinesterase Inhibitors?

A central event in the pathogenesis of Alzheimer's disease (AD) is the accumulation of senile plaques composed of aggregated amyloid-beta (A beta) peptides. The main class of drugs currently used for the treatment of AD are the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. In this study, it has been shown that A beta augmented AChE activity in vitro, maximum activation of 548 +/- 5% was achieved following 48 h of incubation with 10 mu M of A beta(1-40), leading to a 7.7-fold increase in catalytic efficiency. The observed non-competitive type of AChE activation by A beta(1-40) was associated with increased V-max and unchanged K-m. Although BChE activity also increased following incubation with A beta(1-40), this was less efficiently achieved as compared with AChE. Ex vivo electrophysiological experiments showed that 10 mu M of A beta(1-40) significantly decreased the effect of the AChE inhibitor huperzine A on the synaptic potential parameters.

Automated summary

The accumulation of senile plaques composed of aggregated amyloid-beta (A beta) peptides is a central event in the pathogenesis of Alzheimer's disease (AD). Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors are the main class of drugs used for AD treatment. The study shows that A beta can enhance AChE activity and also increase BChE activity, although less efficiently compared to AChE. In addition, A beta can reduce the effect of AChE inhibitors on synaptic potential parameters.