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ARTICLES: R. Squitti, P. Pasqualetti, G. Dal Forno, F. Moffa, E. Cassetta, D. Lupoi, F. Vernieri, L. Rossi, M. Baldassini, and P. M. Rossini Excess of serum copper not related to ceruloplasmin in Alzheimer disease Neurology 2005; 64: 1040-1046 [Abstract] [Full text] [PDF]

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Excess of serum copper not related to ceruloplasmin in Alzheimer disease

Steven R Brenner   (14 June 2005)

Reply to Brenner

Rosanna Squitti, Paolo M. Rossini, Gloria Dal Forno   (14 June 2005)

Excess of serum copper not related to ceruloplasmin in Alzheimer disease 14 June 2005
Steven R Brenner, Department of Neurology St.Louis VA Med. Center, 915 North Grand, St.Louis, MO 63106 Send Correspondence to journal: Re: Excess of serum copper not related to ceruloplasmin in Alzheimer disease SBren20979{at}aol.com Steven R Brenner	I read the article by Squitti et al with interest. [1] I am uncertain of the significance of the non-ceruloplasmin bound copper in the serum of Alzheimer patients. Is it simply a consequence of Alzheimer disease (AD) activity or is directly implicated in the disease process? AD appears to have free copper unbound by ceruloplasmin in increased amounts. This may have clinical implications since treatment with Clinoquinol, a metal-protein-attenuating compound which inhibits zinc and copper ions from binding to Abeta and promotes Abeta dissolution, resulted in minimal deterioration of cognitive scores in treated patients compared to substantial deterioration in patients treated with placebo. [2] Depleted copper levels have been noted to reduce APP production in animals and it is thought the APP regulation of production may represent a target for treatment of AD. [3] The amyloidogenic pathway for Abeta peptides is initiated by BACE1. BACE1 interacts with the copper chaperone for superoxide dismutase-1 and reduces activity of superoxide dismutase through competition for available copper chaperone for superoxide dismutase. [4] Intracellular copper homeostatis is very regulated, since free cuprous ions react with hydrogen peroxide to yield hydroxyl radical. Copper is imported by plasma membrane transport protein and rapidly binds to intracellular copper chaperone proteins. Amyloid precursor protein may be a copper chaperone protein [5] and defective-free cuprous ions would be available to react with hydroxyl radical, a potent oxidative agent. Copper may interact with multiple mechanisms implicated in AD. References 1. Squitti R, Pasqualetti P, Del Forno G, et al. Excess of serum copper not related to ceruloplasmin in Alzheimer disease. Neurology 2005; 64: 1040-1046. 2. Ritchie C, Bush A, Mackinnon A et al. Metal-protein attenuation with iodochlorhydroxyquin (clnoquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disaes: a pilot phase 2 clinical trial. Arch Neurol. 2003; 60: 1685-91. 3. Bellingham S, Lahiri D, Maloney B et al. Copper depletion down- regulates experession of the Alzheimer’s disease amyloid-beta prescursor protein gene. J Biol Chem. 2004; 279: 20378-86. 4. Angeletti B, Waldron K, Freeman K, et al. BACE1 cytoplasmic domain interacts with the copper chaperone for superoxide dismutase-1 and binds copper. J Biol Chem. 2005; 280: 17930-17937. 5. Prohaska J, Gybina A. Intracellular copper transport in mammals. J Nutr. 2004; 134: 1003-1006.
Reply to Brenner 14 June 2005
Rosanna Squitti, Department of Neuroscience AFar-Osp. Fatebenefratelli, Isola Tiberina, 00186 Rome Italy, Paolo M. Rossini, Gloria Dal Forno Send Correspondence to journal: Re: Reply to Brenner rosanna.squitti{at}afar.it Rosanna Squitti, et al.	We thank Dr. Brenner for his letter and agree with all the issues raised. Cues to a direct implication of copper in the pathogenetic process leading to AD, rather than this metal being altered as a mere consequence of the disease process, have been given by a number of clinical trials conducted over the past 15 years. [2,6,7] These trials have provided encouraging results indicating that “metal-protein-attenuating-compounds” can indeed positively modify the natural history of AD. The chelating compound desferrioxamine [6] has demonstrated actual disease slowing effects, while a similar trend has also been shown with the use of clioquinol. [2] However, treatment duration appears to be a fundamental factor, as can it be expected with disease modifying compounds rather than symptomatic approaches. The administration of clioquinol to AD patients for 36 weeks has provided encouraging results, yet these have been far less important than those obtained by the use of desferrioxamine for 24 months. In addition, a 24-week trial with D-penicillamine [7] showed positive effects in reducing, during the administration phase, the oxidative stress that was present at baseline in AD patients However, a significant cognitive effect could not be demonstrated in this short observation period due mostly to lack of measurable cognitive deterioration in the placebo group. We agree with Dr. Brenner that copper is metabolically very finely regulated by the organism and that is precisely why we believe that even a small increase of the serum low molecular weight component can be of a great significance, particularly over a long period of time. When copper is bound to low molecular weight copper compounds, it can be easily exchanged among albumin and small transporter molecules such as peptides or aminoacids. [8] This lability can potentially render copper more toxic and promote oxidative stress, which is significant because these low molecular weight components can easily cross the blood brain barrier. The putative chaperone role of the Amyloid Precursor Protein (APP) has been shown and may be confirmed by our recent observations (manuscript in preparation) demonstrating a relationship between serum levels of copper unbound to ceruloplasmin and beta amyloid in the cerebrospinal fluid in AD patients. References 6. Crapper McLachlan DR, Dalton AJ, Kruck TP, et al. Intramuscular desferrioxamine in patients with Alzheimer’s disease. Lancet 1991; 337: 1304-1308. 7. Squitti R, Rossini PM, Cassetta E, et al. D-penicillamine reduces serum oxidative stress in Alzheimer's disease patients. Eur J Clin Invest. 2002 Jan;32:51-59. 8. Linder MC, Hazegh-Azam M. Copper biochemistry and molecular biology. Am J Clin Nutr 1996;63:797S–811S.