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

• Published in: Cell Vol. 142; no. 6; pp. 857 - 867
• Main Authors: Duce, JA, Tsatsanis, A, Cater, MA, James, SA, Robb, E, Wikhe, K, Leong, S L, Perez, K, Johanssen, T, Greenough, MA, Cho, H H, Galatis, D, Moir, R D, Masters, CL, McLean, C, Tanzi, R E, Cappai, R, Barnham, K J, Ciccotosto, G D, Rogers, J T, Bush, AI
• Format: Journal Article
• Language: English
• Published: 17.09.2010
• ISSN: 0092-8674
• DOI: 10.1016/j.cell.2010.08.014

Alzheimer's Disease (AD) is complicated by pro-oxidant intraneuronal Fe super(2+) elevation as well as extracellular Zn super(2+) accumulation within amyloid plaque. We found that the AD b-amyloid protein precursor (APP) possesses ferroxidase activity mediated by a conserved H-ferritin-like active site, which is inhibited specifically by Zn super(2+). Like ceruloplasmin, APP catalytically oxidizes Fe super(2+), loads Fe super(3+) 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 super(-/-) mice are vulnerable to dietary iron exposure, which causes Fe super(2+) accumulation and oxidative stress in cortical neurons. Paralleling iron accumulation, APP ferroxidase activity in AD postmortem neocortex is inhibited by endogenous Zn super(2+), which we demonstrate can originate from Zn super(2+)-laden amyloid aggregates and correlates with Ab burden. Abnormal exchange of cortical zinc may link amyloid pathology with neuronal iron accumulation in AD.