Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Aβ production in APP23 transgenic mice

doi:10.1073/pnas.2332818100

Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Aβ production in APP23 transgenic mice

^*Department of Psychiatry, Division of Neurobiology, University of the Saarland Medical Center, D-66421 Homburg, Germany; ^‡European Graduate School of Neuroscience, D-6642A Homburg, Germany; ^∥Zentrum fuer Molekulare Biologie der Universität Heidelberg, Im Neuenheimer Feld 282, D-69120 Heidelberg, Germany; ^**Department of Psychiatry, University of Bonn Medical Center, D-53105 Bonn, Germany; ^††Department of Pharmacology, Biocenter, University of Frankfurt, D-60439 Frankfurt, Germany; ^‡‡ABETA GmbH, Heidelberg, Im Neuenheimer Feld 584, D-69120 Heidelberg, Germany; ^§§Novartis Pharma AG, CH-4002 Basel, Switzerland; and ^¶Freie Universitaet Berlin, Institut fuer Chemie/Biochemie, Thielallee 63, D-14195 Berlin, Germany

Edited by Thomas C. Südhof, University of Texas Southwestern Medical Center, Dallas, TX, and approved September 25, 2003 (received for review May 9, 2003)

Abstract

The Cu-binding β-amyloid precursor protein (APP), and the amyloid Aβ peptide have been proposed to play a role in physiological metal regulation. There is accumulating evidence of an unbalanced Cu homeostasis with a causative or diagnostic link to Alzheimer's disease. Whereas elevated Cu levels are observed in APP knockout mice, APP overexpression results in reduced Cu in transgenic mouse brain. Moreover, Cu induces a decrease in Aβ levels in APP-transfected cells in vitro. To investigate the influence of bioavailable Cu, transgenic APP23 mice received an oral treatment with Cu-supplemented sucrose-sweetened drinking water (1). Chronic APP overexpression per se reduced superoxide dismutase 1 activity in transgenic mouse brain, which could be restored to normal levels after Cu treatment (2). A significant increase of brain Cu indicated its bioavailability on Cu treatment in APP23 mice, whereas Cu levels remained unaffected in littermate controls (3). Cu treatment lowered endogenous CNS Aβ before a detectable reduction of amyloid plaques. Thus, APP23 mice reveal APP-induced alterations linked to Cu homeostasis, which can be reversed by addition of dietary Cu.

Footnotes

↵ § To whom correspondence should be addressed at: University of the Saarland Medical Center, Department of Psychiatry, Division of Neurobiology, Building 90, 66421 Homburg/Saar, Germany. E-mail: thomas.bayer{at}uniklinik-saarland.de.
↵ † T.A.B., S.S., and A.S. contributed equally to this work.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: APP, amyloid precursor protein; AD, Alzheimer's disease; CuBD, Cu-binding domain; SOD, superoxide dismutase; ICP-MS, inductively coupled plasma MS.