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

Abstract

The Cu-binding ␤-amyloid precursor protein (APP), and the amyloid A␤ 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 A␤ 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 A␤ 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.

Copper brain homeostasis: Role of amyloid precursor protein and prion protein

“…The above in vivo evidence strongly suggests a beneficial effect for Cu in different AD models (18,19), indicating that Cu could be a positive player in stopping the progress of AD.…”

“…They suggest that cholesterol entering the brain from the circulation of cholesterol-fed rabbits induces the neuronal accumulation Cu 1+ was monitored by the formation of a peak with maximal absorbance at 480 nm in the presence of bathocuproine disulfonic acid. More importantly, Bayer et al (18) showed that bioavailable copper is beneficial to transgenic mice over-expressing human full-length APP with the Swedish mutation (APP23 mice). Whereas aged APP23 transgenic mice showed a dramatically reduced life expectancy within the observation period, Cu-treated APP23 mice did not show this premature death phenotype.…”

Small molecule inhibitors of Aβ‐aggregation and neurotoxicity

“…Cu 21 decreased Ab deposits in APP23 transgenic mice [Bayer et al, 2003] and Ab levels were reduced by a mutant Cu 21 transporter [Phinney et al, 2003]. Additionally, overexpression of human Ab peptides in transgenic mice decreased brain Cu 21 [Maynard et al, 2002].…”

Magnesium in the Central Nervous System

“…Disturbed homeostasis of these biometals in the AD brain (decreased copper levels, and increased concen--trations of iron, zinc, and manganese) has been reported (Cornett et al, 1998;Deibel et al, 1996). An imbalance of zinc and copper has been shown to significantly alter APP processing and Aβ generation in relevant animal models (Bayer et al, 2003;Borchardt et al, 1999;Phinney et al, 2003;Sparks and Schreurs, 2003;Lee et al, 2002;Friedlich et al, 2004).…”

“…Heavy metals (e.g. lead, mercury and cadmium) are neurotoxic and associated with intellectual impairment (Bleecker et al, 2005). Recent studies have implicated lead exposure in the subsequent elevation of APP and Aβ in animals (Basha et al, 2005b) as well as in the aggregation of synthetic Aβ in vitro (Basha et al, 2005a).…”