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The Alzheimer’s therapeutic PBT2 promotes amyloid‐β degradation and GSK3 phosphorylation via a metal chaperone activity
Author(s) -
Crouch Peter J.,
Savva Maria S.,
Hung Lin W.,
Donnelly Paul S.,
Mot Alexandra I.,
Parker Sarah J.,
Greenough Mark A.,
Volitakis Irene,
Adlard Paul A.,
Cherny Robert A.,
Masters Colin L.,
Bush Ashley I.,
Barnham Kevin J.,
White Anthony R.
Publication year - 2011
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2011.07402.x
Subject(s) - extracellular , microbiology and biotechnology , chemistry , phosphorylation , biochemistry , biology
J. Neurochem. (2011) 119 , 220–230. Abstract 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 Ca 2+ /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.