Copper Appears to be Protective against Alzheimer's Disease

Copper has been named as a possible cause of many diseases such as cancer, heart disease, and cancer. However, in every case, more extensive and careful studies found copper to have the opposite action. That is, it reduced the development of such diseases.

Copper was postulated on the basis a few simple studies to be a possible factor in the development of Alzheimer's disease. However, newer, more careful studies, have concluded that copper reduces the development of the disease.

In very recent studies published in November 2003, scientists found that mice with more copper in their brain cells were less likely to develop the toxic protein fragments called amyloid-beta associated with Alzheimer's. In the first study, German scientists found mice with a genetic predisposition to the brain disease lived longer and had less amyloid-beta when they drank copper-containing water than did those that didn't get the extra copper.

In a second study, scientists in Canada and the United States reported that mutant mice with high amounts of copper in their brain cells had half the toxic amyloid-beta buildup as mice without the mutation. The size of the copper reduction of Alzheimer's plaques was as great as that of experimental vaccines that target the harmful proteins.

"There has been the suggestion that elevations of copper can help drive Alzheimer's disease, but we don't get that," said Dr. David Westaway of the University of Toronto. "When we drove up levels of copper in the brain, some of the hallmarks of Alzheimer's disease improved."

Thomas Bayer, a neuroscientist at Saarland University Medical Center, in Homburg/Saar, Germany, and leader of the first study, noted, "If you give mice copper, either in water or by genetic manipulation, you reduce amyloid-beta" and prolong the life of the mice.

Both papers appeared in November of 2003 in the Proceedings of the National Academy of Sciences.

How copper and amyloid-beta reduction are connected is not clear. Bayer's group believes the link involves an enzyme in the brain called beta-amyloid precursor protein, or APP. Copper normally hooks up with this APP protein. But as people age, their copper levels are lessened -- and APP is left without its protective copper. As a result, APP generates the amyloid-beta proteins that destroy neurons.

"If copper is bound to APP, you don't get a-beta protein. If APP is copper-free, toxic a-beta is produced directly," he said. Bayer says the copper connection might help explain of "sporadic" cases of Alzehimer's disease, which account for as much as 95 percent of the total. The rest are due to gene mutations.

An estimated 4.5 million Americans have Alzheimer's disease, according to the Alzheimer's Association. The degenerative disorder has no cure, and drugs on the market to treat it serve only to delay the progression of dementia.

Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14187-14192.
 

Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid A{beta} production in APP23 transgenic mice.

Bayer TA, Schafer S, Simons A, Kemmling A, Kamer T, Tepests R, Eckert A, Schussel K, Eikenberg O, Sturchler-Pierrat C, Abramowski D, Staufenbiel M, Multhaup G.

Department of Psychiatry, Division of Neurobiology, University of the Saarland Medical Center, D-66421 Homburg, Germany.

The Cu-binding beta-amyloid precursor protein (APP), and the amyloid Abeta peptide have been proposed to play a role in physiological metal regulation. There is accumulating evidence of an unbalanced Cu homeostasis with a causative or diagnostic link to Alzheimer's disease. Whereas elevated Cu levels are observed in APP knockout mice, APP overexpression results in reduced Cu in transgenic mouse brain. Moreover, Cu induces a decrease in Abeta levels in APP-transfected cells in vitro. To investigate the influence of bioavailable Cu, transgenic APP23 mice received an oral treatment with Cu-supplemented sucrose-sweetened drinking water (1). Chronic APP overexpression per se reduced superoxide dismutase 1 activity in transgenic mouse brain, which could be restored to normal levels after Cu treatment (2). A significant increase of brain Cu indicated its bioavailability on Cu treatment in APP23 mice, whereas Cu levels remained unaffected in littermate controls (3). Cu treatment lowered endogenous CNS Abeta before a detectable reduction of amyloid plaques. Thus, APP23 mice reveal APP-induced alterations linked to Cu homeostasis, which can be reversed by addition of dietary Cu.

Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14193-14198
 

In vivo reduction of amyloid-{beta} by a mutant copper transporter.

Phinney AL, Drisaldi B, Schmidt SD, Lugowski S, Coronado V, Liang Y, Horne P, Yang J, Sekoulidis J, Coomaraswamy J, Chishti MA, Cox DW, Mathews PM, Nixon RA, Carlson GA, George-Hyslop PS, Westaway D.

Center for Research in Neurodegenerative Diseases, Faculty of Dentistry, Department of Medicine, Division of Neurology, University Health Network, and Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, ON, Canada M5S 3H2.

Cu ions have been suggested to enhance the assembly and pathogenic potential of the Alzheimer's disease amyloid-beta (Abeta) peptide. To explore this relationship in vivo, toxic-milk (txJ) mice with a mutant ATPase7b transporter favoring elevated Cu levels were analyzed in combination with the transgenic (Tg) CRND8 amyloid precursor protein mice exhibiting robust Abeta deposition. Unexpectedly, TgCRND8 mice homozygous for the recessive txJ mutation examined at 6 months of age exhibited a reduced number of amyloid plaques and diminished plasma Abeta levels. In addition, homozygosity for txJ increased survival of young TgCRND8 mice and lowered endogenous CNS Abeta at times before detectable increases in Cu in the CNS. These data suggest that the beneficial effect of the txJ mutation on CNS Abeta burden may proceed by a previously undescribed mechanism, likely involving increased clearance of peripheral pools of Abeta peptide.