Therapeutic Redistribution of Metal Ions To Treat Alzheimer's Disease

Currently, therapeutics that modify Alzheimer's disease (AD)are not available. Increasing age is the primary risk factor for AD and due to an aging global population the urgent need for effective therapeutics increases every year. This Account presents the development of an AD treatment strategy that incorporates diverse compounds with a common characteristic: the ability to redistribute metal ions within the brain. Central to cognitive decline in AD is the amyloid-beta peptide (A beta) that accumulates in the AD brain. A range of therapeutic strategies have been developed based on the premise that decreasing the brain A beta burden will attenuate the severity of the disease symptoms. Unfortunately these treatments have failed to show any positive outcomes in large-scale clinical trials, raising many questions regarding whether therapeutics for AD can rely solely on decreasing A beta levels. An alternate strategy is to target the interaction between A beta and metal ions using compounds with the potential to redistribute metal ions within the brain. The original rationale for this strategy came from studies showing that metal ions promote A beta toxicity and aggregation. In initial studies using the prototype metal-chelating compound dioquinol (CQ), CO prevented A beta toxicity in vitro, out-competed A beta for metal ions without affecting the activity of metal-dependent enzymes, and attenuated the rate of cognitive decline in AD subjects in a small phase II clinical trial. All these outcomes were consistent with the original hypothesized mechanism of action for CQ where prevention or reversal of the extracellular A beta-metal interactions could prevent A beta toxicity. Soon after the completion of these studies, a new body of work began to suggest that this hypothesized mechanism of action for CQ was simplistic and that other factors were also important for the positive therapeutic outcomes. Perhaps most significantly, it was shown that after CQ sequesters metal ions the neutral CQ-metal complex crosses cell membranes to increase intracellular levels of the metals, thereby initiating protective cell signaling cascades. The activity of CQ therefore appeared to be two-fold: it prevented toxic interactions between A beta and metal ions outside the cell, and it redistributed the metal ions into the cell to promote healthy cell function. To determine the significance of redistributing metal ions into the cell, glyoxalbis(N(4)-methylthiosemicarbazonato)Cu-II [Cu-II(gtsm)] was tested in models of AD. Cu-II(gtsm) delivers Cu into cells, but, unlike CQ it cannot out-compete A beta for metal ions. When tested in AD model mice, the Cull(gtsm) treatment restored cognitive function back to levels expected for cognitively healthy mice. The most advanced compound from this therapeutic strategy, PBT2, can sequester metal ions from A beta and redistribute them into the cell like CQ. PBT2 improved cognition in a phase II clinical trial with AD patients, and further clinical testing is currently underway.