title: Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease.
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.
authors.affiliation: Mental Health Research Institute, The University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: James A
authors.initials: JA
authors.lastname: Duce
authors.forename: Andrew
authors.initials: A
authors.lastname: Tsatsanis
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cater
authors.forename: Simon A
authors.initials: SA
authors.lastname: James
authors.forename: Elysia
authors.initials: E
authors.lastname: Robb
authors.forename: Krutika
authors.initials: K
authors.lastname: Wikhe
authors.forename: Su Ling
authors.initials: SL
authors.lastname: Leong
authors.forename: Keyla
authors.initials: K
authors.lastname: Perez
authors.forename: Timothy
authors.initials: T
authors.lastname: Johanssen
authors.forename: Mark A
authors.initials: MA
authors.lastname: Greenough
authors.forename: Hyun-Hee
authors.initials: HH
authors.lastname: Cho
authors.forename: Denise
authors.initials: D
authors.lastname: Galatis
authors.forename: Robert D
authors.initials: RD
authors.lastname: Moir
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Catriona
authors.initials: C
authors.lastname: McLean
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.forename: Roberto
authors.initials: R
authors.lastname: Cappai
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barnham
authors.forename: Giuseppe D
authors.initials: GD
authors.lastname: Ciccotosto
authors.forename: Jack T
authors.initials: JT
authors.lastname: Rogers
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002570:Ceruloplasmin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D051379:Mice; D016415:Sequence Alignment; D015032:Zinc / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D007501:Iron; D002570:Ceruloplasmin; D015032:Zinc
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