Though considerable effort has been spent over the last few decades investigating the relationship between Alzheimer's disease and aluminum, the role of the transition metal remains controversial. Today, evidence presented in the Journal of Neuroscience strengthens the case for the involvement of a different metal, copper, in the etiology of AD.
An international team of researchers, led by Roberto Cappai, University of Melbourne, challenged cultures of cortical neurons with copper-bound full-length amyloid precursor protein (AβPP), or metallated fragments of the protein, and found a dose-dependent relationship between the amount of added protein-Cu and cell death. Furthermore, the neurotoxicity of AβPP-Cu was dramatically enhanced by low-density lipoprotein (LDL); in its presence, more than twice the number of cells died upon exposure to fivefold less AβPP-Cu.
The authors localized the toxic property of AβPP to amino acids 124-189, which contain the copper-binding domain. This fragment induced cell death and oxidation of LDL when bound to copper. They also found that not all APPs are equally potent. Most toxic were isoforms that contain histidines 147 and 151, which are proposed to chelate the copper atom, while isoforms with one histidine are inert, and those with the histidines replaced by tyrosine and lysine (for example C. elegans APL-1) can actually protect cells against copper-mediated damage.
"This is a very interesting paper that continues to build on the idea that amyloid can bind copper and takes us a step further toward understanding the mechanism of amyloid toxicity and oxidative damage," comments James Connor, Penn State University. However, he cautions that the role of copper may be quite complex. In Menke's and other diseases where copper levels are substantially elevated, no evidence for accelerated dementia has been found.—Tom Fagan
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- White AR, Multhaup G, Galatis D, McKinstry WJ, Parker MW, Pipkorn R, Beyreuther K, Masters CL, Cappai R. Contrasting, species-dependent modulation of copper-mediated neurotoxicity by the Alzheimer's disease amyloid precursor protein. J Neurosci. 2002 Jan 15;22(2):365-76. PubMed.