Degradation of Amyloid-ß Species by Multi-Copper Oxidases.

ABSTRACT

Background: Reduction of the production of amyloid-ß (Aß) species has been intensively investigated as potential therapeutic approaches for Alzheimer's disease (AD). However, the degradation of Aß species, another potential beneficial approach, has been far less explored. Objective: To investigate the potential of multi-copper oxidases (MCOs) in degrading Aß peptides and their potential benefits for AD treatment. Methods: We investigated the degradation efficiency of MCOs by using electrophoresis and validated the ceruloplasmin (CP)-Aß interaction using total internal reflection fluorescence microscopy, fluorescence photometer, and fluorescence polarization measurement. We also investigated the therapeutic effect of ascorbate oxidase (AO) by using induced pluripotent stem (iPS) neuron cells and electrophysiological analysis with brain slices. Results: We discovered that CP, an important MCO in human blood, could degrade Aß peptides. We also found that other MCOs could induce Aß degradation as well. Remarkably, we revealed that AO had the strongest degrading effect among the tested MCOs. Using iPS neuron cells, we observed that AO could rescue neuron toxicity which induced by Aß oligomers. In addition, our electrophysiological analysis with brain slices suggested that AO could prevent an Aß-induced deficit in synaptic transmission in the hippocampus. Conclusions: To the best of our knowledge, our report is the first to demonstrate that MCOs have a degrading function for peptides/proteins. Further investigations are warranted to explore the possible benefits of MCOs for future AD treatment.