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-β 
peptide (Aβ) that accumulates in the AD brain. A range of therapeutic strategies 
have been developed based on the premise that decreasing the brain Aβ 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 Aβ levels. An alternate strategy is to target the 
interaction between Aβ 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 Aβ toxicity and 
aggregation. In initial studies using the prototype metal-chelating compound 
clioquinol (CQ), CQ prevented Aβ toxicity in vitro, out-competed Aβ 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 Aβ-metal 
interactions could prevent Aβ 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 Aβ 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 Aβ for metal ions. When tested in AD model mice, the Cu(II)(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 Aβ 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.