Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease.
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.
Duce
James A
JA
Mental Health Research Institute, The University of Melbourne, Parkville, Victoria 3052, Australia.
Tsatsanis
Andrew
A
Cater
Michael A
MA
James
Simon A
SA
Robb
Elysia
E
Wikhe
Krutika
K
Leong
Su Ling
SL
Perez
Keyla
K
Johanssen
Timothy
T
Greenough
Mark A
MA
Cho
Hyun-Hee
HH
Galatis
Denise
D
Moir
Robert D
RD
Masters
Colin L
CL
McLean
Catriona
C
Tanzi
Rudolph E
RE
Cappai
Roberto
R
Barnham
Kevin J
KJ
Ciccotosto
Giuseppe D
GD
Rogers
Jack T
JT
Bush
Ashley I
AI
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*
D016564:Amyloid beta-Protein Precursor; D007501:Iron; D002570:Ceruloplasmin; D015032:Zinc
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