Amine oxidase activity of β-amyloid precursor protein modulates systemic and local catecholamine levels.
The catecholamines dopamine (DA), norepinephrine (NE) and epinephrine (E) are neurotransmitters and hormones that mediate stress responses in tissues and plasma. The expression of β-amyloid precursor protein (APP) is responsive to stress and is high in tissues rich in catecholamines. We recently reported that APP is a ferroxidase, subsuming, in neurons and other cells, the iron-export activity that ceruloplasmin mediates in glia. Here we report that, like ceruloplasmin, APP also oxidizes synthetic amines and catecholamines catalytically (K(m) NE=0.27 mM), through a site encompassing its ferroxidase motif and selectively inhibited by zinc. Accordingly, APP knockout mice have significantly higher levels of DA, NE and E in brain, plasma and select tissues. Consistent with this, these animals have increased resting heart rate and systolic blood pressure as well as suppressed prolactin and lymphocyte levels. These findings support a role for APP in extracellular catecholaminergic clearance.
The Mental Health Research Institute, The University of Melbourne, Parkville, VIC, Australia.
J A
JA
Duce
S
S
Ayton
A A
AA
Miller
A
A
Tsatsanis
L Q
LQ
Lam
L
L
Leone
J E
JE
Corbin
H
H
Butzkueven
T J
TJ
Kilpatrick
J T
JT
Rogers
K J
KJ
Barnham
D I
DI
Finkelstein
A I
AI
Bush
D016564:Amyloid beta-Protein Precursor / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D002395:Catecholamines / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000633:toxicity; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008995:Monoamine Oxidase / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects
D016564:Amyloid beta-Protein Precursor; D002395:Catecholamines; D008995:Monoamine Oxidase; D004298:Dopamine