Impaired metal ion homeostasis causes synaptic dysfunction and treatments for 
Alzheimer's disease (AD) that target metal ions have therefore been developed. 
The leading compound in this class of therapeutic, PBT2, improved cognition in a 
clinical trial with AD patients. The aim of the present study was to examine the 
cellular mechanism of action for PBT2. We show PBT2 induces inhibitory 
phosphorylation of the α- and β-isoforms of glycogen synthase kinase 3 and that 
this activity is dependent on PBT2 translocating extracellular Zn and Cu into 
cells. This activity is supported when Aβ:Zn aggregates are the source of 
extracellular Zn and adding PBT2 to Aβ:Zn preparations promotes Aβ degradation 
by matrix metalloprotease 2. PBT2-induced glycogen synthase kinase 3 
phosphorylation appears to involve inhibition of the phosphatase calcineurin. 
Consistent with this, PBT2 increased phosphorylation of other calcineurin 
substrates, including cAMP response element binding protein and 
Ca²⁺/calmodulin-dependent protein kinase. These data demonstrate PBT2 can 
decrease Aβ levels by sequestering the Zn that promotes extracellular formation 
of protease resistant Aβ:Zn aggregates, and that subsequent intracellular 
translocation of the Zn by PBT2 induces cellular responses with synapto-trophic 
potential. Intracellular translocation of Zn and Cu via the metal chaperone 
activity of PBT2 may be an important mechanism by which PBT2 improves cognitive 
function in people with AD.