Iron-Export Ferroxidase Activity of β-Amyloid Precursor Protein is Inhibited by Zinc in Alzheimer's Disease

JA Duce; A Tsatsanis; MA Cater; SA James; E Robb; K Wikhe; SL Leong; K Perez; T Johanssen; MA Greenough; HH Cho; D Galatis; RD Moir; CL Masters; C McLean; RE Tanzi; R Cappai; KJ Barnham; GD Ciccotosto; JT Rogers; AI Bush

Journal article

Iron-Export Ferroxidase Activity of β-Amyloid Precursor Protein is Inhibited by Zinc in Alzheimer's Disease

JA Duce, A Tsatsanis, MA Cater, SA James, E Robb, K Wikhe, SL Leong, K Perez, T Johanssen, MA Greenough, HH Cho, D Galatis, RD Moir, CL Masters, C McLean, RE Tanzi, R Cappai, KJ Barnham, GD Ciccotosto, JT Rogers Show all

Cell | CELL PRESS | Published : 2010

DOI: 10.1016/j.cell.2010.08.014

Abstract

Alzheimer's Disease (AD) is complicated by pro-oxidant intraneuronal Fe2+ elevation as well as extracellular Zn2+ accumulation within amyloid plaque. We found that the AD β-amyloid protein precursor (APP) possesses ferroxidase activity mediated by a conserved H-ferritin-like active site, which is inhibited specifically by Zn2+. Like ceruloplasmin, APP catalytically oxidizes Fe2+, loads Fe3+ into transferrin, and has a major interaction with ferroportin in HEK293T cells (that lack ceruloplasmin) and in human cortical tissue. Ablation of APP in HEK293T cells and primary neurons induces marked iron retention, whereas increasing APP695 promotes iron export. Unlike normal mice, APP-/- mice are vu..

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University of Melbourne Researchers

Timothy Johanssen Author

Catriona McLean Author

Kevin Barnham Author

Joe Ciccotosto Author

Grants

Awarded by National Institute on Aging

Funding Acknowledgements

This work was supported by funds from the National Institute on Aging (1RO1AG12686), the Australian Research Council, the Australian National Health & Medical Research Council (NHMRC), Operational Infrastructure Support Victorian State Government, and the Alzheimer's Association. The Victorian Brain Bank Network is supported by The University of Melbourne, The Mental Health Research Institute, The Alfred Hospital, and the Victorian Forensic Institute of Medicine and funded by Neurosciences Australia and the NHMRC. We thank Gerd Multhaup for helpful comments and for providing APP reagents for pilot studies, Paul Adlard for human tissue samples, and Wilma Wasco for the APLP2 construct. C. L. M., R. E. T., K.J.B., and A. I. B. are shareholders, paid consultants, and advisory board members of Prana Biotechnology Ltd. A.I.B. is a shareholder of Cogstate Ltd and Eucalyptus Biosciences Pty Ltd. M. A. C. is a shareholder in Prana Biotechnology Ltd.