After years as a potential but peripheral suspect in the pathogenesis of Alzheimer's disease, copper (Cu) is lobbying for a new designation—potential therapy! Two studies in the November 17 PNAS Early Edition suggest that copper can increase life expectancy and reduce amyloid plaque load in APP transgenic mice.
Both copper and the Aβ peptide have Cu binding sites, and there is evidence that Cu can enhance Aβ aggregation, adding weight to the long-held belief that copper is a destructive force in the pathophysiology of Alzheimer's (see ARF related news story; ARF news story). Still, Borchardt and colleagues showed tantalizing evidence in 1999 that Cu could reduce Aβ production in vitro (Borchardt et al., 1999). Other evidence suggests—not unexpectedly—that the story is even more complicated (see ARF related news story).
In one of the current papers, Thomas Bayer of the University of Saarland, Homburg, Germany, and colleagues at several other German institutions have tested this question in vivo. The researchers compared the effects of adding Cu (in a sugar solution) to the diet of APP23 transgenic mice (which overexpress APP) and their nontransgenic littermates. They found that without the dietary Cu, APP23 mice had significantly reduced life expectancies, a problem that did not exist in the APP23 mice receiving Cu. The researchers also assessed Cu levels in the brains of the mice, both by inductively coupled plasma MS and by the indirect route of assaying the activity of the Cu-dependent antioxidant enzyme SOD1. Both measures indicated that APP-overexpressing mice had depleted brain Cu levels, but these could be restored to control levels by the Cu-containing diet.
In regard to Aβ, Bayer and colleagues found that Cu treatment lowered endogenous CNS Aβ—before the age at which reductions in amyloid plaque burden was observed. The authors note previous evidence that APP may be involved in lowering intracellular Cu levels, and write that "deleterious effects of APP23 overexpression are likely due to an interference with Cu homeostasis and intracellular Cu trafficking."
Also in the November 17 PNAS Early Edition, David Westaway, Amie Phinney, and colleagues report a different approach to manipulating copper levels in vivo. They examined APP-overexpressing TgCRND8 mice, along with mice transgenic for a mutant Cu transporting enzyme (ATPase7b) that raises Cu levels, and crosses of these two. As with the study by Bayer and colleagues, Westaway's team noted that the APP transgenic mice had reduced levels of brain copper, despite their high plaque and Aβ levels. On the other hand, the Cu transporter gene mutant mice (termed tx[J]), with their higher levels of Cu, had lower levels of Aβ than did controls. In the crossbred TgCRND8/tx[J/J] mice, the researchers found that the increased Cu reduced mortality led to a 45 percent reduction in plaques containing human Aβ, reduced plasma levels of Aβ, and reduced endogenous mouse Aβ. The authors suggest that the mechanism by which the tx[J] mutation lowers Aβ may involve changing peripheral Aβ catabolism, with subsequent effects on the brain Aβ pool.—Hakon Heimer