AN ANTIBIOTIC that removes metals from the brain is emerging as a prime candidate for treating Alzheimer鈥檚. This boosts a controversial theory that blames the accumulation of metals, rather than the formation of insoluble plaques, for the disease鈥檚 characteristic mental deterioration.
The antibiotic, clioquinol, binds to copper and zinc, and is small enough to get into the brain. It is no longer manufactured but was last used in the 1970s to treat intestinal infections. Now Ashley Bush and his colleagues at Harvard Medical School, the University of Melbourne and Prana Biotechnology in Melbourne are trying to resurrect the drug to treat Alzheimer鈥檚.
The company will soon publish results from a phase II trial. Full details haven鈥檛 been revealed yet, but Prana says the results are 鈥渆xtremely encouraging鈥�. In patients given clioquinol, the progression of the disease slowed down and levels of beta amyloid protein, which clumps together to form the plaques, were significantly reduced, it says.
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What鈥檚 more, last week the researchers presented fresh evidence about how the treatment works. Lab tests show that clioquinol inhibits one of beta amyloid鈥檚 rogue activities: churning out toxic hydrogen peroxide.
That fits neatly with an emerging, fringe theory (快猫短视频, 26 August 2000, p 36). Bush鈥檚 team thinks that Alzheimer鈥檚 starts when metals such as copper, iron and zinc accumulate in the brain and turn beta amyloid into a rogue enzyme that catalyses the production of hydrogen peroxide.
As beta amyloid continues to bind to the metals, it forms long chains that eventually become insoluble plaques. But in Bush鈥檚 view, the plaques are a symptom of the disease, not the cause. He thinks it is the hydrogen peroxide that wreaks havoc in brain cells.
If Bush is right, removing metals from the brain should slow down and even reverse the disease, because beta amyloid should revert to its harmless form and stop making peroxide. He thinks this is what鈥檚 happening in Alzheimer鈥檚 patients on clioquinol. 鈥淭he science has become very solid,鈥� says Bush.
But his theory is controversial, not just because it proposes a different cause for the disease, but also because it suggests that treatments that target amyloid plaques are misdirected. Most researchers still believe that plaques are key players in the disease.
Bush responds that the best way to prove his hypothesis is by finding a drug that works. 鈥淎nd we have,鈥� he says. 鈥淲e have gone from bench to clinic, and the clinical trial is all about testing the hypothesis.鈥�
鈥淚 think [Bush鈥檚 theory] is incredibly innovative,鈥� says George Perry of Case Western Reserve University in Ohio. He points out that a drug that not only binds to metal but also acts as an antioxidant to mop up hydrogen peroxide could be even more effective.
The full results of the trials will be eagerly awaited, especially as other potential treatments for Alzheimer鈥檚 are falling away. There was much excitement about Elan Pharmaceuticals鈥� vaccine, which was designed to provoke an immune response that destroys plaques. But in March the company stopped a trial after several patients developed brain inflammation.
Big hopes also rest on secretase inhibitors, designed to prevent the beta amyloid protein forming in the first place. But the inhibitors may not be as specific as once thought, and could block the formation of other, critical proteins.
There are safety concerns about clioquinol, too. The antibiotic was taken off the market after thousands of patients developed a neurological disease. It was later suggested this was caused by the depletion of vitamin B12 in people whose levels were already low. Bush believes that such problems can be avoided by giving patients B12 supplements, as Prana has been doing in the current trials.