Degradation of Amyloid-β Species by Multi-Copper Oxidases

Article type: Research Article

Authors: Yang, Jing^{a; b} | Ran, Kathleen^a | Ma, Wenzhe^c | Chen, Yanshi^a | Chen, Yanxin^a | Zhang, Can^d | Ye, Hui^e | Lu, Ying^{c; *} | Ran, Chongzhao^{a; *}

Affiliations: [a] Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital/Harvard Medical School, Charlestown, Boston, MA, USA | [b] School of Engineering, China Pharmaceutical University, Nanjing, China | [c] Department of System Biology, Harvard Medical School, Boston, MA, USA | [d] Department of Neurology, Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA | [e] Department of Biology, Loyola University Chicago, IL, USA

Correspondence: [*] Correspondence to: Chongzhao Ran, Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital/Harvard Medical School, Room 2301, Building 149, Charlestown, Boston, MA 02129, USA. E-mail: cran@nmr.mgh.harvard.edu and Ying Lu, Department of System Biology, Harvard Medical School, Boston, MA 02115, USA. E-mail: ying_lu@hms.harvard.edu.

Abstract: Background:Reduction of the production of amyloid-β (Aβ) species has been intensively investigated as potential therapeutic approaches for Alzheimer’s disease (AD). However, the degradation of Aβ species, another potential beneficial approach, has been far less explored. Objective:To investigate the potential of multi-copper oxidases (MCOs) in degrading Aβ peptides and their potential benefits for AD treatment. Methods:We investigated the degradation efficiency of MCOs by using electrophoresis and validated the ceruloplasmin (CP)-Aβ 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 Aβ peptides. We also found that other MCOs could induce Aβ 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 Aβ oligomers. In addition, our electrophysiological analysis with brain slices suggested that AO could prevent an Aβ-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.

Keywords: Alzheimer’s disease, amyloid-β degradation, ascorbate oxidase, ceruloplasmin

DOI: 10.3233/JAD-240625

Journal: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 525-539, 2024