Degradation of amyloid beta by multi‐copper oxidases

Abstract

AbstractBackgroundThe accumulation of amyloid beta (Aβ) species has been widely considered to be one of the possible causes of the pathology of Alzheimer’s disease (AD). Inhibiting Aβ production to prevent the accumulation and aggregation has been intensively investigated. However, the degradation of Aβ, which can also reduce the accumulation, has received much less attentions.MethodIn this study, we used FAM‐Aβ42, a fluorescent dye conjugated Aβ, to investigate the degradation of Aβ in the presence of various multi‐copper oxidases.ResultWe first discovered that ceruloplasmin (CP), the major copper‐carrying protein in the blood, could degrade Aβs. We then validated the CP‐Aβ interaction using total internal reflection fluorescence (TIRF) microscopy, fluorescence photometer and fluorescence polarization measurement. We further found that the presence of Vitamin C could enhance the degrading effect in a concentration‐dependent manner. Based on the above discovery, we hypothesized that other multi‐copper oxidases (MCO) had similar Aβ‐degrading function. Indeed, we found that other MCOs could induce Aβ cleavage. Remarkably, we revealed that ascorbate oxidase (AO) had the strongest degrading effect amony the tested MCOs. Using iPS‐induced neuron cells, we observed that AO could rescue cell apoptosis and neuron toxicity which induced by Aβ oligmers. In addition, our electrophysiological analysis with brain slides suggested that AO could prevent an Aβ induced deficit in synaptic transmission in the hippocampus.ConclusionTo the best of our knowledge, our report is the first to demonstrate that MCOs could bind to Aβs and mediate cleavage of Aβs. Further investigations are warranted to explore the possible benefits of the Aβ‐degrading function of MCOs.