Copper and clioquinol treatment in young APP transgenic and wild-type mice: effects on life expectancy, body weight, and metal-ion levels.
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, counteracting the supposed therapeutic effects of CQ as an agent for chelating therapy in AD.
Schäfer
Stephanie
S
Department of Psychiatry, Division of Neurobiology, Saarland University, Homburg, Germany.
Pajonk
Frank-Gerald
FG
Multhaup
Gerd
G
Bayer
Thomas A
TA
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D001835:Body Weight / Q000187:drug effects*; D002614:Chelating Agents / Q000494:pharmacology; D007464:Clioquinol / Q000494:pharmacology*; D003300:Copper / Q000378:metabolism* / Q000494:pharmacology; D008017:Life Expectancy; D008670:Metals / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002614:Chelating Agents; D008670:Metals; D003300:Copper; D007464:Clioquinol