title: Metal chaperones prevent zinc-mediated cognitive decline.
abstract: Zinc transporter-3 (ZnT3) protein is responsible for loading zinc into presynaptic vesicles and consequently controls the availability of zinc at the glutamatergic synapse. ZnT3 has been shown to decline with age and in Alzheimer's disease (AD) and is crucially involved in learning and memory. In this study, we utilised whole animal behavioural analyses in the ZnT3 KO mouse line, together with electrophysiological analysis of long-term potentiation in brain slices from ZnT3 KO mice, to show that metal chaperones (clioquinol, 30 mg/kg/day for 6weeks) can prevent the age-dependent cognitive phenotype that characterises these animals. This likely occurs as a result of a homeostatic restoration of synaptic protein expression, as clioquinol significantly restored levels of various pre- and postsynaptic proteins that are critical for normal cognition, including PSD-95; AMPAR and NMDAR2b. We hypothesised that this clioquinol-mediated restoration of synaptic health resulted from a selective increase in synaptic zinc content within the hippocampus. While we demonstrated a small regional increase in hippocampal zinc content using synchrotron x-ray fluorescence microscopy, further sub-region analyses are required to determine whether this effect is seen in other regions of the hippocampal formation that are more closely linked to the synaptic plasticity effects observed in this study. These data support our recent report on the use of a different metal chaperone (PBT2) to prevent normal age-related cognitive decline and demonstrate that metal chaperones are efficacious in preventing the zinc-mediated cognitive decline that characterises ageing and disease.
authors.affiliation: The Florey Institute for Neuroscience and Mental Health and The University of Melbourne, Parkville, Victoria 3052, Australia. Electronic address: paul.adlard@florey.edu.au.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Adlard
authors.affiliation: The Mental Health Research Institute, Parkville, Victoria 3052, Australia.
authors.forename: Jacqui
authors.initials: J
authors.lastname: Parncutt
authors.affiliation: The Mental Health Research Institute, Parkville, Victoria 3052, Australia.
authors.forename: Varsha
authors.initials: V
authors.lastname: Lal
authors.affiliation: Australian Synchrotron and the CSIRO Preventative Health Flagship, Clayton, Victoria 3168, Australia.
authors.forename: Simon
authors.initials: S
authors.lastname: James
authors.affiliation: Elemental Bio-imaging Centre, University of Technology Sydney, Broadway, New South Wales 2007, Australia.
authors.forename: Dominic
authors.initials: D
authors.lastname: Hare
authors.affiliation: Elemental Bio-imaging Centre, University of Technology Sydney, Broadway, New South Wales 2007, Australia.
authors.forename: Philip
authors.initials: P
authors.lastname: Doble
authors.affiliation: The Florey Institute for Neuroscience and Mental Health and The University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: David I
authors.initials: DI
authors.lastname: Finkelstein
authors.affiliation: The Florey Institute for Neuroscience and Mental Health and The University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D027682:Cation Transport Proteins; D007464:Clioquinol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003072:Cognition Disorders / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004924:Escape Reaction / Q000187:drug effects / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D015032:Zinc / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D027682:Cation Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C531955:PBT2 compound; C491177:Slc30a3 protein, mouse; D007464:Clioquinol; D015032:Zinc
keywords: Animal model; Clioquinol; Cognition; Zinc; ZnT3