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 SOD-1. 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

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  1. Cobbold et al. find that Menkes disease protein is enriched in the plasma membrane in the presence of excess copper, and that trafficking of MNK from the TGN to the plasma membrane is inhibited by Cdc42 and WASP. Cdc42 and N-WASP are increased in AD (Zhu et al., 2000; Kitamura et al., 2003).

    Might Aβ become a copper transporter when MNK remains at the TGN? Might the addition of copper enable relocalization of MNK to the plasma membrane, thus reducing the need for Aβ to act as a copper transporter?

    References:

    . Novel membrane traffic steps regulate the exocytosis of the Menkes disease ATPase. Hum Mol Genet. 2002 Nov 1;11(23):2855-66. PubMed.

    . Activation of oncogenic pathways in degenerating neurons in Alzheimer disease. Int J Dev Neurosci. 2000 Jul-Aug;18(4-5):433-7. PubMed.

    . Possible involvement of Wiskott-Aldrich syndrome protein family in aberrant neuronal sprouting in Alzheimer's disease. Neurosci Lett. 2003 Aug 7;346(3):149-52. PubMed.

  2. Comment by Rebecca J. Henderson and James R. Connor
    Much attention has been paid to the link between AD and metal ions. These studies go back to the imbalance of iron found in the brain in AD and the contribution of iron to oxidative stress [1], and even earlier to the idea that aluminum toxicity was involved in the pathogenesis of AD. More recently, data have been presented indicating that β-amyloid has a relatively high binding affinity for zinc, iron, and copper. Metal complexing agents are under investigation as therapeutic agents in Alzheimer’s disease [2,3]. Because metals are acquired through dietary and environmental sources, one mechanism by which metal availability could be manipulated is through the diet. Three recent papers published in PNAS attempt to elucidate more clearly copper’s effect, if any, on the disease state. Two of the papers [4,5] propose beneficial actions for copper, while work by Sparks and Schruers [6] claims that dietary copper exacerbates the disease.

    Phinney et al. use a potentially powerful technique of crossing two transgenic animal models in order to evaluate how a propensity for higher uptake of copper may impact the deposition of amyloid. The result was an unexpected decrease in plaque burden in the animals with the mutation that should increase copper levels. The data are promising and reveal important areas for future study, but have some limitations. In these types of studies it is important to show that the changes in the amount of total brain copper or any metal are occurring in the same regions as alterations in amyloid expression, processing or plaque burden. It is difficult to reconcile, for example, how the lack of any change in copper concentration at two months of age (Figure 2) can be directly related to a change in Aβ (Figure 5) when the combined transgenic animals have an increase in brain copper but no difference in the Aβ brain concentrations (Figures 3b and d). The plasma decreases of Aβ noted in the study are interesting and worthy of pursuit. However, at this time a relationship between plasma Aβ and brain Aβ has not been established. The authors attempt to address the concern about the distribution of copper and plaques by providing the data in Figure 4. However, in order to interpret these data as directly relevant to copper, the concentrations of copper in the hippocampus must be determined. Nonetheless, the authors have shown that elevations in total brain copper do not increase plaque burden or Aβ levels in brain, which warrants further investigation.

    Bayer et al. [5] provide provocative data of a possible sex-linked difference in response to dietary copper. Their data illustrating a reduction in lethality after copper administration is impressive. However, the increase of brain copper levels the researchers aimed to achieve was barely significant above control levels. Furthermore, as in the Phinney et al. study, the regional levels of copper and changes in the other parameters are critical to understanding any potential relationship. The substantial error bars make the data in this study difficult to evaluate.

    The final PNAS paper on which we are offering comment found that trace amounts of copper in the drinking water can increase markers of AD in the brain in cholesterol-fed rabbits [6]. Although in apparent contrast to the previous two papers, it must be remembered that these rabbits were cholesterol-fed. There is no control group for copper without cholesterol, so the direct contribution of copper is not clear. A significant experimental design concern with this study is the amount of copper administered. As mentioned in the paper, 0.9 mg./day of copper is the EPA’s normal tolerable upper limit for the metal. The rabbits in this study consumed between 0.04 and 0.08 mg./day based on average amount of water ingested. If the rabbits weighed 2.2 kg., this would be equivalent to a 1.2 to 2.4 mg./day dose of copper for a 150 lb. human, well above the EPA limit. Therefore, the applicability of this study to humans exposed to normal levels of environmental copper is questionable, as is the relationship to AD pathogenesis. High cholesterol, and high copper plus high cholesterol could induce AD-like morphological changes in the brain, whereas according to the previous two studies, high copper alone may actually be protective. Therefore, in the context of the previous papers, the data from the study by Sparks and Schreurs could be interpreted to indicate that decreasing cholesterol should be the goal in a copper-rich environment.

    These studies underscore the importance of an environmental or dietary factor in the induction of AD-like pathology in the brain and are important, given the low number of genetic mutations associated with AD. The data offer compelling evidence that investigations into the contribution of biometals to AD and clinical studies involving metal chelation therapy in AD are worthy of support.

    See also:

    Connor, J.R., ed. Metals and Oxidative Damage in Neurological Disorders. 1997, Plenum Press: New York.

    Malecki, E.A. and J.R. Connor, The case for iron chelation and/or antioxidant therapy in Alzheimer's disease. Drug Development Research, 2002. 51: p. 1-5.

    References:

    . Copper, zinc, and the metallobiology of Alzheimer disease. Alzheimer Dis Assoc Disord. 2003 Jul-Sep;17(3):147-50. PubMed.

    . In vivo reduction of amyloid-beta by a mutant copper transporter. Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14193-8. PubMed.

    . Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Abeta production in APP23 transgenic mice. Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14187-92. PubMed.

    . Trace amounts of copper in water induce beta-amyloid plaques and learning deficits in a rabbit model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):11065-9. PubMed.

References

News Citations

  1. Coping with Copper—Minute Amount of Metal Plagues Rabbit Brain
  2. Two Ways to Attack Amyloid: Metal Chelator and Antibody
  3. Good Copper, Bad Copper: News on this Metal's Role in Alzheimer's

Paper Citations

  1. . Copper inhibits beta-amyloid production and stimulates the non-amyloidogenic pathway of amyloid-precursor-protein secretion. Biochem J. 1999 Dec 1;344 Pt 2:461-7. PubMed.

Further Reading

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Primary Papers

  1. . Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Abeta production in APP23 transgenic mice. Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14187-92. PubMed.
  2. . In vivo reduction of amyloid-beta by a mutant copper transporter. Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14193-8. PubMed.