ORIGINAL ARTICLE Copper and clioquinol treatment in young APP transgenic and wild-type mice: effects on life expectancy, body weight, and metal-ion levels Stephanie Schäfer & Frank-Gerald Pajonk & Gerd Multhaup & Thomas A. Bayer Received: 6 July 2006 / Revised: 25 August 2006 / Accepted: 8 November 2006 / Published online: 9 January 2007 # Springer-Verlag 2007 Abstract There is mounting evidence that the amyloid precursor protein (APP), the key protein in Alzheimer ’ s disease (AD) is involved in the copper (Cu) homeostasis in the brain. Conflicting results about the potential use of dietary Cu and clioquinol (CQ), a known Cu chelator, have been reported using APP transgenic mice. Previously, in vitro studies have demonstrated that CQ can act as a Cu transporter. To analyze the potential function of CQ as a Cu transporter in vivo, the nutritional effect of Cu and CQ was analyzed in young APP transgenic mice and nontransgenics with food pellets containing either Cu, CQ, Cu plus CQ (Cu + CQ), or without addition of supplements (control). The offspring were fed with corresponding food pellets until the age of 14 weeks. We observed an increased lethality of APP transgenics upon CQ treatment, which could be rescued by a co-treatment with Cu. The exposure of Cu + CQ led to a modest but significant increase in cerebral Cu levels, most likely due to an enhanced transport of CQ–Cu complexes. In CQ or Cu + CQ treatment groups, the plasma levels of Cu, zinc, and iron were reduced in all animals; moreover, Cu treatment alone reduced only plasma iron levels. We conclude not only that CQ has certain toxicity but also that the chelating effect, perhaps, plays a secondary role with respect to its properties as an intracellular Cu transporter, thus, counter- acting the supposed therapeutic effects of CQ as an agent for chelating therapy in AD. Keywords Clioquinol . Cu . Metal homeostasis . APP . Transgenic mice Abbreviations Cu copper CQ clioquinol Fe iron Al aluminium Zn zinc J Mol Med (2007) 85:405–413 DOI 10.1007/s00109-006-0140-7 S. Schäfer : F.-G. Pajonk : T. A. Bayer (*) Department of Psychiatry, Division of Neurobiology, Saarland University, Homburg, Germany e-mail: thomas.bayer@uniklinik-saarland.de G. Multhaup Institute for Biochemistry, Free University of Berlin, Berlin, Germany STEPHANIE SCHÄFER received her PhD in neurosci- ence from the Saarland Univer- sity, Germany. Her research interests included transgenic approaches for studying the in- fluence of copper and gender on APP metabolism. She is pres- ently postdoc at the Abbott GmbH & CoKG, Germany. THOMAS A. BAYER received his Ph.D. in Develop- mental Biology from the Uni- versity of Cologne, Germany. He is presently an Associate Professor of Molecular Neuro- biology at the Saarland Univer- sity, Germany. His research interests include the identifica- tion of the molecular basis of neurodegeneration and thera- peutical prevention of Alz- heimer's disease using molecular neuropathology, animal models, and clinical approaches.