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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
1
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pubmed:dateCreated |
2011-9-12
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pubmed:abstractText |
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 ?- and ?-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 A?:Zn aggregates are the source of extracellular Zn and adding PBT2 to A?:Zn preparations promotes A? 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 A? levels by sequestering the Zn that promotes extracellular formation of protease resistant A?: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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Amyloid beta-Peptides,
http://linkedlifedata.com/resource/pubmed/chemical/Calcineurin,
http://linkedlifedata.com/resource/pubmed/chemical/Caspase 3,
http://linkedlifedata.com/resource/pubmed/chemical/Clioquinol,
http://linkedlifedata.com/resource/pubmed/chemical/Copper,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Glycogen Synthase Kinase 3,
http://linkedlifedata.com/resource/pubmed/chemical/Matrix Metalloproteinase 2,
http://linkedlifedata.com/resource/pubmed/chemical/Metals,
http://linkedlifedata.com/resource/pubmed/chemical/Molecular Chaperones,
http://linkedlifedata.com/resource/pubmed/chemical/PBT2 compound,
http://linkedlifedata.com/resource/pubmed/chemical/Peptide Hydrolases,
http://linkedlifedata.com/resource/pubmed/chemical/Zinc
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
1471-4159
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pubmed:author |
pubmed-author:AdlardPaul APA,
pubmed-author:BarnhamKevin JKJ,
pubmed-author:BushAshley IAI,
pubmed-author:ChernyRobert ARA,
pubmed-author:CrouchPeter JPJ,
pubmed-author:DonnellyPaul SPS,
pubmed-author:GreenoughMark AMA,
pubmed-author:HungLin WLW,
pubmed-author:MastersColin LCL,
pubmed-author:MotAlexandra IAI,
pubmed-author:ParkerSarah JSJ,
pubmed-author:SavvaMaria SMS,
pubmed-author:VolitakisIreneI,
pubmed-author:WhiteAnthony RAR
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pubmed:copyrightInfo |
© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.
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pubmed:issnType |
Electronic
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pubmed:volume |
119
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
220-30
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pubmed:meshHeading |
pubmed-meshheading:21797865-Alzheimer Disease,
pubmed-meshheading:21797865-Amyloid beta-Peptides,
pubmed-meshheading:21797865-Blotting, Western,
pubmed-meshheading:21797865-Calcineurin,
pubmed-meshheading:21797865-Caspase 3,
pubmed-meshheading:21797865-Cell Line, Tumor,
pubmed-meshheading:21797865-Clioquinol,
pubmed-meshheading:21797865-Copper,
pubmed-meshheading:21797865-Enzyme Inhibitors,
pubmed-meshheading:21797865-Glycogen Synthase Kinase 3,
pubmed-meshheading:21797865-Humans,
pubmed-meshheading:21797865-Mass Spectrometry,
pubmed-meshheading:21797865-Matrix Metalloproteinase 2,
pubmed-meshheading:21797865-Metals,
pubmed-meshheading:21797865-Molecular Chaperones,
pubmed-meshheading:21797865-Peptide Hydrolases,
pubmed-meshheading:21797865-Phosphorylation,
pubmed-meshheading:21797865-Zinc
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pubmed:year |
2011
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pubmed:articleTitle |
The Alzheimer's therapeutic PBT2 promotes amyloid-? degradation and GSK3 phosphorylation via a metal chaperone activity.
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pubmed:affiliation |
Department of Pathology, The University of Melbourne, Victoria, Australia. pjcrouch@unimelb.edu.au
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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