A solution to Alzheimer's disease?

β-Amyloid (Aβ) deposits visualized in adjacent sections of Alzheimer's-disease-affected cortex by Aβ immunohistochemistry (lower panel) and using a fluorescent marker (TSQ) for zinc (upper panel). Courtesy of A. I. Bush, Harvard Medical School, Massachusetts, USA.

Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid peptide (Aβ) in the neocortex and other brain regions; preventing or reversing the build-up of this peptide could be central to the effective treatment of the disorder. Aβ has high- and low-affinity binding sites for Cu²⁺ and Zn²⁺ — ions which are elevated in the neocortex of AD patients, particularly in amyloid plaques. The binding of Cu²⁺ and Zn²⁺ to Aβ is thought to mediate its reversible precipitation and its resistance to proteases. For this reason, Cu/Zn chelators have clear potential as a treatment for AD, as Cherny and colleagues report in Neuron.

In a previous study, Cherny et al. showed that Cu/Zn chelators can solubilize Aβ in post-mortem brain tissue from AD patients. In view of these promising results, they went on to examine the effects of a bioavailable (lipophilic) Cu/Zn chelator — clioquinol — on Aβ deposits in a transgenic mouse model (APP2576) of AD. Like other Cu/Zn-selective chelators, clioquinol could inhibit and reverse the Cu/Zn-mediated aggregation of synthetic Aβ in vitro, and could solubilize Aβ deposits in post-mortem AD brain samples. In transgenic mice with advanced Aβ deposition, the oral administration of clioquinol for as little as nine weeks was associated with significantly lower levels of sedimentable Aβ per wet weight of cerebral tissue, accompanied by an increase in the quantities of soluble Aβ. A decrease in amyloid plaque surface area was also observed in clioquinol-treated animals, and serum levels of Aβ were found to be lower in these mice compared with sham-treated controls. Treatment with clioquinol did not seem to be associated with any adverse reactions; in fact, the authors reported a significant improvement in scores on a general behaviour rating scale.

Cherny et al. argue that the effects of clioquinol contrast favourably with those of other candidate treatments tested in transgenic mouse models of AD, including the Aβ vaccination approach. In particular, they point to the relatively large reduction in the absolute quantities of Aβ after clioquinol treatment, and to the speed with which this drug achieves its beneficial effects. They suggest that clioquinol or its derivatives be investigated further as a means of treating or preventing the disorder. Important issues that will need to be addressed include the possibility that increased levels of soluble Aβ might also contribute to pathophysiology in AD. A phase II clinical trial of clioquinol in AD patients is now in progress.