ARTICLE IN BRIEF
Researchers found a four-fold increase in levels of copper in the brain capillaries of an Alzheimer's disease mouse model.
Copper appears to promote Alzheimer's disease by disrupting the transport of toxic amyloid-beta (Abeta) across the blood-brain barrier and into blood, according to new research by Rashid Deane, PhD, and colleagues at the University of Rochester Medical Center. The accumulation of Abeta in the brain is assumed to promote its aggregation into the senile plaques characteristic of Alzheimer's disease (AD).
Even the low levels of copper found in drinking water were sufficient to disrupt the activity of lipoprotein receptor-related protein 1 (LRP1), which facilitates the transport of Abeta across the blood-brain barrier, the investigators reported in the Aug. 19 online edition of the Proceeding of the National Academy of Sciences.
The researchers found high levels of copper in the brain capillaries of an AD mouse model, according to Dr. Deane, research professor in the department of neurosurgery at the University of Rochester Medical Center.
Dr. Deane and his colleagues found a four-fold increase in copper in the brain capillaries isolated from aging mice that drank water containing copper, and a two-fold decrease in LRP1 levels. Meanwhile, levels of Abeta 40 and 42 in the mouse brains rose by 50 percent, even though no significant change was found in brain levels of amyloid precursor protein.
“We found an accumulation in the vessels, not in the parenchyma itself,” he said. “Abeta must bind to LRP1 on the endothelial cells — the cells of the blood-brain barrier — to get transported across the membrane to the blood on the other side. If the level of LRP1 is reduced, then Abeta transport is reduced, and the accumulation of this peptide in the brain may eventually result in deposits and plaques.”
Normally, LRP1 binds with Abeta and escorts it from the brain, but this function was severely disrupted in mice that drank water for three months containing amounts of copper found in city water supplies — an amount about 90 percent lower than the maximum allowed by the Environmental Protection Agency. Rather than entering the brain, the copper accumulated in the capillary walls, where it caused nitration of LRP1, which damaged the protein and inhibited its ability to transport toxic Abeta from the brain to the blood supply for disposal.
In addition to delivering a one-two punch by promoting the creation of Abeta and inhibiting its disposal, copper also provoked inflammation of the brain, another common AD symptom.
Dr. Deane emphasized that the effect of low levels of copper delivered to the aging mice in their drinking water is not inherently dangerous. “We used water because it's a convenient way to administer copper to animals, nothing more than that,” he said. “I'm not saying the water supply is bad, or that copper piping is dangerous. Copper has been around for a long time. Are we getting too much of it? That's worth thinking about. Maybe too much of a good thing is bad.”
Commenting on the study, Ashley I. Bush, MD, PhD, who is involved in studying copper's effects on the brain, said that, unlike aluminum — another metal implicated in Alzheimer's — copper is a vital nutrient involved in many normal bodily functions including neural transmission, blood oxygenation, and the formation of connective tissue, so inhibiting it must be done with extreme care. Dr. Bush, who was not involved in the current study, has been working on developing PBT2, a “chaperone” molecule designed to escort copper from the brain. (Results of a phase 2 clinical trial of PBT2 are expected shortly.)
“In Alzheimer's, the handling of copper is abnormal as reflected in other things such as mitochondrial function, which certainly needs copper,” said Dr. Bush, director of the Oxidation Biology Laboratory at the Florey Institute for Neuroscience and Mental Health in Melbourne, Australia, and professor of pathology at the University of Melbourne.
“Normally, copper is very tightly bound to various protein complexes,” he said. “The brain keeps very stringent homeostatic control over the movement of copper into the cell and within the cell. In Alzheimer's disease, however, it looks as though the copper in brain tissue becomes loosened up and available for abnormal exchange, which sets up conditions where it could end up in wrong place and disrupt LRP1, which is what these researchers are proposing as a mechanism of interaction of copper with Abeta.”
But the effect of copper on the LRP1 protein seems to provide a very persuasive mechanism that accounts for how the metal contributes to Alzheimer's pathology, said Dr. Bush. “It looks like they've found a smoking gun,” said Dr. Bush. “It might be that as you get older, you become exquisitely sensitive to copper in your diet and in your water.”
Still, treatment that involves removing copper from the brain will be tricky, according to Joseph S. Beckman, PhD, principal investigator and Ava Helen Pauling Chair at the Linus Pauling Institute, and distinguished professor in the department of biochemistry and biophysics at Oregon State University, and director of the University's Environmental Health Sciences Center.
“You have to be careful about pulling copper out of tissues because copper is essential for life,” said Dr. Beckman, who emphasized that the brain needs copper. A chelator that pulled too much copper from the body could disrupt neurotransmitters, he said, and thereby affect behavior. “You want to manage copper very carefully,” he said.
According to Dr. Bush, that is the challenge posed by the results produced by Dr. Deane and his colleagues. “I think the results look very clear,” he said. “There is a big interaction of copper with Alzheimer-relevant biological systems, and this work shows us how sensitive that interaction is. The interaction does not seem to involve a simple copper overload problem due to overexposure to copper. However, since the Abeta clearance machinery is remarkably sensitive to copper, exposure to too much copper could lead to the accumulation of beta-amyloid in the brain.”
“The fact that copper prevents the pleating of amyloid-beta has been known for 10 years, and yet that seems to be continuously ignored,” said Christopher Exley, PhD, a professor in bioinorganic chemistry with the Keefe University's Birchall Centre in Staffordshire in the UK. “The implication is that copper accelerates deposition of amyloid-beta in senile plaques. We know that at least in vitro, the opposite happens.”
Dr. Exley said that in his own research, “we don't see any elevation of copper in either the aged or the Alzheimer brain. We have been able to look at correlations between amyloid-beta deposition and the load of copper and we get an inverse relationship. Where there's high copper, we find lower amounts of beta-amyloid pleated sheets.”
The small amounts of capillary tissue measured by Dr. Deane and his colleagues may have produced misleading measures of copper, according to Dr. Exley.
“Measuring metals in tissues is not a trivial thing at all,” he said. “The lower the amount of tissue the higher the amount of metal is measured. We don't know why that is. The distribution of certain metals is not homogenous within tissue, so it's hard to get reliable data without sufficient tissue. In our human brain studies, if we do not have a minimum of 250 mg wet weight of tissue, we cannot get a reliable result. Now, 250 mg of mouse artery — I can't imagine how many mice you would need to get that weight of artery.” (Dr. Deane and his colleagues used the concentrated capillaries from 1,000 mg of mouse brain tissue in some analyses.)
Nevertheless, Dr. Exley believes the results reported by Dr. Deane and his colleagues provide valuable information about the effect of copper on the blood-brain barrier. “They've highlighted the possibility that copper is accumulating preferentially in brain capillaries. This is a good group, and Rashid is a good scientist. I just feel there are so many unanswered questions that the results are not straightforward.”