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PMID: 20817278 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease.

Cell ·Vol. 142 ·No. 6 ·2010-09-17 ·Pages 857-67

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

Abstract

Alzheimer's Disease (AD) is complicated by pro-oxidant intraneuronal Fe(2+) elevation as well as extracellular Zn(2+) 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 Zn(2+). Like ceruloplasmin, APP catalytically oxidizes Fe(2+), loads Fe(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(-/-) mice are vulnerable to dietary iron exposure, which causes Fe(2+) accumulation and oxidative stress in cortical neurons. Paralleling iron accumulation, APP ferroxidase activity in AD postmortem neocortex is inhibited by endogenous Zn(2+), which we demonstrate can originate from Zn(2+)-laden amyloid aggregates and correlates with Aβ burden. Abnormal exchange of cortical zinc may link amyloid pathology with neuronal iron accumulation in AD.

MeSH Terms
Alzheimer Disease/metabolism,pathology Amino Acid Sequence Amyloid beta-Protein Precursor/antagonists & inhibitors,chemistry,metabolism Animals Cell Line Ceruloplasmin/antagonists & inhibitors,chemistry,metabolism Humans Iron/metabolism Mice Sequence Alignment Zinc/metabolism
Chemicals
Amyloid beta-Protein Precursor Iron Ceruloplasmin Zinc
Authors & Affiliations
21 authors, click to expand affiliations / ORCID
Duce James A
Mental Health Research Institute, The University of Melbourne, Parkville, Victoria 3052, Australia.
Tsatsanis Andrew
Cater Michael A
James Simon A
Robb Elysia
Wikhe Krutika
Leong Su Ling
Perez Keyla
Johanssen Timothy
Greenough Mark A
Cho Hyun-Hee
Galatis Denise
Moir Robert D
Masters Colin L
McLean Catriona
Tanzi Rudolph E
Cappai Roberto
Barnham Kevin J
Ciccotosto Giuseppe D
Rogers Jack T
Bush Ashley I
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2010.08.014
Published
2010-09-17
Pages
857-67
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC2943017
Subset
IM
Grants
NIA NIH HHS · R01 AG012686 · United States
NIA NIH HHS · R01 AG012686-10 · United States
NIA NIH HHS · 1R01AG12686 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2010.08.014 PMC Full Text View journal details
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