Copper Damages Protein That Defends Against Alzheimer's

The research by neuroscientists at the University of Rochester Medical Center was presented at the annual meeting of the Society for Neuroscience in San Diego Nov. 3-7, 2007. The work was highlighted as part of a press conference on potential environmental influences on Alzheimer's disease.

For decades, many scientists have hypothesized that a variety of metals, including aluminum, iron, zinc and copper, might play a role in Alzheimer's disease, but no link has ever been proven. In the past few years, several scientists have reported that copper is one component of the amyloid beta clumps --tiny trash heaps filled with all sorts of molecules and substances -- that speckle the brains of people with Alzheimer's disease.

The new results go much further, showing that copper damages the major known system the brain uses to get rid of amyloid beta. The find marks perhaps the first time that scientists have found a specific way -- a "molecular mechanism" -- that a metal could contribute to the disease process in Alzheimer's disease.

"Metals like aluminum have been suspected for years, but the mechanism through which metals might act has been unclear," said Rashid Deane, Ph.D., the lead author of the work who presented the results in San Diego. "We've demonstrated one mechanism through which copper increases levels of amyloid beta in the brain, by damaging the molecule that gets rid of the substance."

The team found that copper damages a molecule known as LRP (low-density lipoprotein receptor-related protein), a molecule that acts like an escort service in the brain, shuttling amyloid-beta out of the brain and into the body. The molecule's role in Alzheimer's was revealed more than a decade ago by another author of the work, Berislav Zlokovic, M.D., Ph.D., professor of Neurosurgery and Neurology and director of the Frank P. Smith Laboratory for Neuroscience and Neurosurgery Research. Zlokovic is widely recognized for demonstrating that blood vessels, blood flow, and the blood-brain barrier are central to the development of Alzheimer's disease.

The study was done in mice as well as on cells from the brains of people who died from Alzheimer's disease. Deane's team compared mice that drank water containing trace amounts of water (.12 milligrams per liter, less than one-tenth the 1.3 mg/l level of copper allowed in drinking water by the Environmental Protection Agency), to mice that drank distilled water.

Mice that drank water with trace levels of copper had about twice as much copper in the cells lining the blood vessels of the brain as the mice that did not. They also had about one-third fewer LRP molecules in those blood vessels and about one-third more amyloid beta in their brains than the control mice, after 10 weeks.

Using human cells, the team discovered that copper damages the protein LRP to such an extent that it stops working. The team has shown previously that having fewer functioning LRP molecules results in higher levels of amyloid beta, which ultimately aggregates together and kills brain cells.

"We all have some amyloid beta in the brain normally," said Deane, associate professor of Neurological Surgery. "When you age, a little bit more accumulates in the brain naturally. But the process is greatly accelerated in people with Alzheimer's disease."

While it's clear from the study that copper can damage LRP, Deane says it's preliminary to draw the conclusion that copper causes Alzheimer's disease based on the study.

"There's a great deal more work that needs to be done to fully understand the role that copper may play in Alzheimer's disease," said Deane. "We need to explore the mechanism of how copper breaks down LRP much more fully. Then, of course, we must see if the same is true in people. There are different ways to measure copper in the blood, and indeed, there is some research linking low levels of copper to Alzheimer's, while there is other research linking high levels of copper to the disease."

Deane emphasizes that having appropriate levels of copper in our body is crucial for our health. Copper helps keep our bones our strong and our skin toned, and it helps our nerves fire crisply and our cells to generate the energy we need to live. It helps keep our blood healthy so we can get the oxygen we need to all our organs. And it plays a role in keeping our immune system strong.

While drinking water is the most obvious source of copper in our diet, because of copper pipes, the substance is also quite common in red meat, nuts, shellfish, and many fruits and vegetables.

The research highlights the importance of the blood-brain barrier, an intricate filtering mechanism that lines the inside of blood vessels inside the brain and is designed to keep toxic substances out. It's as if the ultra-sensitive brain is designed to be isolated from the common blood supply. Thousands of molecules act as sentries, decided exactly which substances are allowed into and out of the brain, and which aren't allowed to cross the barrier. LRP is one such sentry, specializing in the removal of amyloid beta from the brain.

"The body needs to maintain the environment of the brain pristinely so that our brain cells stay healthy and are able to function effectively," said Deane. "It's the job of the blood-brain barrier to keep the brain safe and healthy. It may very well be a breakdown with the barrier that is at the root of Alzheimer's disease."

In addition to Deane and Zlokovic, others who contributed to the study include post-doctoral researchers Abhay Sagare, Ph.D., Mireia Coma, Ph.D., and Itender Singh, Ph.D.; and technical associates Bob Gelein and Margaret Parisi.

The work was funded by the Alzheimer's Association and by the National Institute of Environmental Health Sciences.