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Amine oxidase activity of β-amyloid precursor protein modulates systemic and local catecholamine levels

Molecular Psychiatry volume 18, pages 245–254 (2013)Cite this article

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Abstract

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 (Km 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.

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Acknowledgements

We thank Michael Cater for the generation of FD1(E415N)-APP695 and Keyla Perez for the generation of the FD1 peptide. This work was supported by funds from the Australian Research Council, the Australian National Health & Medical Research Council and the Alzheimer's Association.

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Authors and Affiliations

  1. The Mental Health Research Institute, The University of Melbourne, Parkville, VIC, Australia

    J A Duce, S Ayton, A Tsatsanis, L Q Lam, K J Barnham, D I Finkelstein & A I Bush

  2. Center for Neuroscience, The University of Melbourne, Parkville, VIC, Australia

    J A Duce, S Ayton, H Butzkueven, T J Kilpatrick & D I Finkelstein

  3. Department of Pharmacology, Monash University, Clayton, VIC, Australia

    A A Miller

  4. Department of Pathology, The University of Melbourne, Parkville, VIC, Australia

    L Leone, K J Barnham & A I Bush

  5. The Walter and Eliza Hall Institute of Medical Research & the Cooperative Research for Cellular Growth Factors, PO Royal Melbourne Hospital, Parkville, VIC, Australia

    J E Corbin

  6. Department of Psychiatry, Massachusetts General Hospital, Charlestown, MA, USA

    J T Rogers

  7. Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia

    K J Barnham

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  1. J A Duce
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Correspondence to A I Bush.

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Competing interests

AIB, DIF and KJB are shareholders and paid consultants for Prana Biotechnology. AIB is a shareholder in Brighton Biotech, and paid consultant for Adeona. JAD and AIB have received speaking honoraria from Amgen. The remaining authors declare no conflict of interest.

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Duce, J., Ayton, S., Miller, A. et al. Amine oxidase activity of β-amyloid precursor protein modulates systemic and local catecholamine levels. Mol Psychiatry 18, 245–254 (2013). https://doi.org/10.1038/mp.2011.168

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