. 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.

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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.

    View all comments by Mary Reid
  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.

    View all comments by Rebecca J. Henderson