Cell
Volume 142, Issue 6, 17 September 2010, Pages 857-867
Journal home page for Cell

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

https://doi.org/10.1016/j.cell.2010.08.014Get rights and content
Under an Elsevier user license
open archive

Summary

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 vulnerable to dietary iron exposure, which causes Fe2+ accumulation and oxidative stress in cortical neurons. Paralleling iron accumulation, APP ferroxidase activity in AD postmortem neocortex is inhibited by endogenous Zn2+, which we demonstrate can originate from Zn2+-laden amyloid aggregates and correlates with Aβ burden. Abnormal exchange of cortical zinc may link amyloid pathology with neuronal iron accumulation in AD.

Highlights

► APP is a H-ferritin-like ferroxidase and similarly inhibited by zinc ► APP has a major interaction with ferroportin, facilitating iron export from neurons ► APP−/− mice have elevated hippocampal and cortical neuronal iron and oxidation ► In AD cortex, zinc trapped by accumulated Aβ inhibits APP ferroxidase activity

HUMDISEASE
MOLNEURO
CELLBIO

Cited by (0)

8

These authors contributed equally to this work

9

Present address: Research Division, The Peter MacCallum Cancer Centre, St. Andrew's Place, East Melbourne, Victoria 3002, Australia