According to Ashley Bush of Harvard Medical School, Aβ is rapidly precipitated by Zn2+ at low physiological concentrations, and Cu2+ and Fe3+ also induce Aβ aggregation. Zn/Cu-selective chelators markedly enhance the solubilization of Aβ deposits from postmortem AD brains, and Dr. Bush and his colleagues have purified Aβ from human brain showing that it is metallated with Zn and Cu. Hence, Aβ should be regarded as a metalloprotein. Zinc, copper, and iron are markedly elevated in the AD brain, and are especially highly concentrated in Aβ deposits in humans and in APP transgenic mice. When it binds Cu2+ or Fe3+, Aβ reduces the metal ions and produces H2O2 by electron transfer to O2. This is important because of growing evidence for oxidation injury in AD, and Aβ cytotoxicity could be mediated by Cu2+:Aβ interactions that generate H2O2 which can be blocked by chelators.
For these reasons, Dr. Bush and colleagues have pursued metal-Aβ interactions as a target for therapeutics, and they recently reported that Aβ1-42 possesses an attomolar affinity Cu2+ binding site that is among the strongest known, and similar to the affinity of Cu2+ for the antioxidant enzyme superoxide dismutase 1. They also found that the Cu2+-mediated H2O2 production by Aβ is suppressed by cobinding of Zn2+, and indeed, despite precipitating Aβ into amyloid, Zn2+ rescues Aβ neurotoxicity in cell culture. These and other studies have led them to conclude that AD amyloid plaques may represent the redox-silencing and entombment of Aβ by zinc. Hence, the plaques may not be the pathogenic culprit in AD, and evidence suggests that the toxic forms of Aβ may be the soluble or diffuse Aβ collections in the brain.
On the basis of growing information about Zn2+ and Cu2+ interactions with Aβ mediating the biochemistry of Aβ, Dr. Bush and colleagues recently embarked on a trial of copper-chelators to attempt to inhibit Aβ accumulation in APP2576 transgenic mice. Treatment with clioquinol (CQ), a retired antibiotic and bioavailable Cu/Zn chelator, induced a 49% decrease in brain Aβ deposition in a blinded study of APP2576 transgenic mice treated orally for nine weeks. There was no evidence of neurotoxicity or increased non-amyloid pathology. The drug may work by a combined action that facilitates disaggregation of the Aβ collections, while also inhibiting H2O2 production. Importantly, CQ treatment did not induce a loss in metal levels systemically, probably because it is a relatively weak chelator and the metals are redistributed rather than excreted. Thus, CQ treatment appears to be a potent inhibitor of Aβ accumulation. CQ may be the first credible drug candidate based on the amyloid hypothesis of AD, and Dr. Bush reported that a phase II double-blind clinical trial on the effects of CQ in AD patients is currently in progress.—John Trojanowski.
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