|
||||||||
|
PATHOLOGY An Alternate Take on Alzheimer'sOxidation of Trace Metals in Brain Might Cause Disease The cause of Alzheimer's disease remains unsolved, but one theory argues that the answer to this biological puzzle lies in inorganic substances that few biomedical researchers bother to study—metals. Research led by Ashley Bush, HMS associate professor of psychiatry at Massachusetts General Hospital, questions some of the paradigms of Alzheimer's research and offers a very different model for the pathology of the disease, involving the oxidation of trace metals in the brain. Although it has been difficult for Bush and his colleagues to gain acceptance for the ideas they have been developing for years, a new study in the June 21 Neuron backs up their in vitro studies with in vivo results and a potential therapy.
Is copper undervalued? Research by Ashley Bush suggests the oft-neglected trace metals copper and zinc may play pivotal roles in Alzheimer's disease. Photo by Steve Gilbert Much of Alzheimer's research has focused on the role of the protein amyloid-beta, found at high levels in the brains of Alzheimer's patients. Researchers have tried to understand why the protein, which is a ubiquitous substance in all tissues, inexplicably coagulates into plaques in the brain. The protein's longest form, for instance, has properties that make it particularly self-aggregating, so researchers have speculated that high levels may contribute to disease. Bush, who heads the Laboratory for Oxidation Biology at MGH, has focused instead on how oxidation can inflict damage on cells, especially in Alzheimer's. Oxidative damage has been observed in Alzheimer's disease, but it has not been clear whether it actually causes neurodegeneration or is simply a side effect of A-beta's toxicity. Bush believes that oxidation is in fact the real culprit of Alzheimer's dementia. According to his model, oxidative stress results from an improper interaction of A-beta with copper and zinc, which exist naturally in the neocortex of the brain and have been found at elevated levels in Alzheimer's plaques. A Toxic ReactionA-beta has a high affinity for zinc and especially copper, and Bush's lab has used in vitro studies to show that A-beta reacts with copper to produce hydrogen peroxide, which is toxic to cells. Zinc can suppress this reaction between copper and A-beta, preventing neurotoxicity. These opposing reactions suggest that there may be a balance between the two that gets disrupted in Alzheimer's disease, allowing oxidation to prevail.One of the strong points of this theory is that it offers an explanation for an unsolved mystery: why does A-beta—which is found throughout the body and brain—exist? "I can't believe nature would go to so much trouble to generate such an abundant protein that has no function but to cause Alzheimer's disease," Bush said. His lab has found that A-beta binds to metals like copper and zinc, forming a structure similar to superoxide dismutase, a molecule that uses metals to catalyze antioxidant reactions. In fact, Bush believes that this metal binding might indicate a natural role for A-beta as an antioxidant. Superoxide dismutase can also exist in a mutated form that causes it to malfunction and produce an oxidation reaction, which is linked to the neurodegenerative disorder amyotrophic lateral sclerosis (Lou Gehrig's disease). Benign Plaques?One of the most surprising implications of this theory is that it questions the very idea that plaques are damaging. Scientists have assumed that the ominous amyloid plaques riddling the brains of Alzheimer's patients are associated with neurological damage. But in fact, Bush argues, "there's never been a very good correlation between the abundance of plaques and the nature of the dementia." Rather, dementia may be correlated with levels of soluble A-beta in the brain, not with the amount of plaque.On the contrary, Bush believes that plaques may represent a protective event, a sort of holding cell for A-beta that prevents it from inflicting oxidative damage on cells. Zinc, in addition to preventing hydrogen peroxide production, also rapidly precipitates A-beta, causing it to aggregate. So zinc may be acting as a vigilante, incarcerating A-beta so it is unavailable to interact with copper. Proof of PrincipleThough the theory of oxidation and metal interactions has been seen as a marginal player and needs further study to clarify these mechanisms, Bush has recently made his theory stronger with evidence that this reaction can be targeted by a drug that binds to copper and zinc. His group used clioquinol, a retired antibiotic, in a mouse model of Alzheimer's. The mice, which are engineered to overproduce A-beta, were treated with the drug for nine weeks, after which they had a 49 percent decrease in A-beta deposition. The treated mice also showed an improvement in general health after only a couple of weeks.Bush credits the rapid effects to reduced oxidation rather than clearing of A-beta. If A-beta is prevented from interacting with metals and producing hydrogen peroxide, the normal mechanisms for clearing A-beta may be able to function more robustly. —Courtney Humphries |
