title: The Alzheimer's therapeutic PBT2 promotes amyloid-β degradation and GSK3 phosphorylation via a metal chaperone activity.
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 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.
authors.affiliation: Department of Pathology, The University of Melbourne, Victoria, Australia. pjcrouch@unimelb.edu.au
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crouch
authors.forename: Maria S
authors.initials: MS
authors.lastname: Savva
authors.forename: Lin W
authors.initials: LW
authors.lastname: Hung
authors.forename: Paul S
authors.initials: PS
authors.lastname: Donnelly
authors.forename: Alexandra I
authors.initials: AI
authors.lastname: Mot
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Parker
authors.forename: Mark A
authors.initials: MA
authors.lastname: Greenough
authors.forename: Irene
authors.initials: I
authors.lastname: Volitakis
authors.forename: Paul A
authors.initials: PA
authors.lastname: Adlard
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cherny
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barnham
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D015153:Blotting, Western; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D007464:Clioquinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D003300:Copper / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D013058:Mass Spectrometry; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008670:Metals / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015032:Zinc / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D008670:Metals; D018832:Molecular Chaperones; C531955:PBT2 compound; D003300:Copper; D007464:Clioquinol; D038362:Glycogen Synthase Kinase 3; D019703:Calcineurin; D010447:Peptide Hydrolases; D053148:Caspase 3; D020778:Matrix Metalloproteinase 2; D015032:Zinc