Journal Club

Highlighting recently published papers selected by Academy members

A penny for your thoughts: How copper could contribute to dementia

As an element, copper is known for its above-average ability to conduct electricity and heat, making it a key component of wires and cables that speedily transmit information and messages from place to place. But in the brain, too much copper could have just the opposite effect, disrupting the brain’s normally zippy signaling. A PNAS Early Edition paper has concluded that excess copper encourages the formation of amyloid plaques, clumps of proteins in the brain that are thought to contribute to Alzheimer’s disease.

“We now know that copper contributes to the buildup of amyloid in the brain,” says Rashid Deane of the University of Rochester Medical Center, senior author of the new paper. “I think Alzheimer’s is a multifactorial disease, so copper certainly doesn’t cause all cases, but it’s likely a contributing factor.”

In living organisms, some amount of copper is necessary; a number of proteins require the element to function. People get trace amounts of copper into their bodies by eating a diverse array of foods including asparagus, mushrooms, liver, nuts, and chocolate. But too much copper can poison someone, causing liver and kidney damage.

Previous studies have found increased levels of copper in the brains of older animals, but hadn’t specified where in the brain the buildup was occurring. And experiments on isolated cells found that copper could bind to amyloid, the protein that accumulates in the brains of Alzheimer’s patients. With these two pieces of data in mind, Deane and his colleagues wondered what effect copper could be having on brain physiology.

“Every animal has a blood-brain barrier to restrict what can go in and out of the brain,” Deane says. “And so copper really shouldn’t be going into the brain.”

Deane’s team measured the copper in the brains of young and old mice and found that, in healthy animals, copper wasn’t in fact accumulating inside brain cells. Instead, it was building up in the blood vessels just outside the blood-brain barrier, where it got blocked from moving any further. The researchers found that aging mice had four times more copper in these brain capillaries than young mice. And when they fed water dosed with low levels of copper (below what’s considered contaminant levels by the Environmental Protection Agency) to young mice, they once again saw accumulation in the brain’s blood vessels. And in these vessels, in both cases, the copper was wreaking havoc.

A protein called LRP1 that normally shuttles amyloid out of the brain was being damaged by the high levels of copper in the blood vessels of the aging mice, Deane discovered.

“We are constantly producing new amyloid and the amyloid is also constantly being cleared from the brain,” Deane says. “LRP1 normally ferries the amyloid out. Without it, amyloid accumulates in the brain.” And when amyloid accumulates, he says, it forms the aggregates that are hallmarks of Alzheimer’s disease.

The researchers next tested whether the story was any different in animals that already had Alzheimer’s. They dosed the mice’s water with copper and then measured where the copper ended up. But this time, it didn’t just accumulate in blood vessels. The excess copper leaked through the blood-brain barrier and attached itself to amyloid proteins, where it encouraged the formation of amyloid plaques by cross-linked the proteins to each other.

“It’s a double whammy,” Deane explains. “The copper not only builds up in blood vessels as it does in normal mice, but it also gets into the brain when the animals already have disease.” This means that high copper levels could contribute to both the development and the progression of Alzheimer’s disease, he says.

The researchers haven’t yet tested whether the copper levels can be directly associated with development of progression of dementia symptoms, but think the connection between copper and amyloid suggests a connection. And more studies on levels of copper in people, instead of mice, are needed to more fully understand its role in human disease.

But Dean’s hope is that the finding will help lead to novel ideas on how to prevent or treat Alzheimer’s. Since copper’s initial damage to the brain’s blood vessels, and the LRP amyloid transporter, is happening through oxidation of LRP, antioxidants like vitamin A and vitamin C–which counteract oxidation–could block this damage.

“I don’t want to send the message to the public to stop eating any foods containing copper,” says Deane. “A better message would be to make sure you’re getting enough antioxidants.”

Categories: Neuroscience
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