Metal chaperones prevent zinc-mediated cognitive decline

Adlard, PA; Parncutt, J; Lal, V; James, S; Hare, D; Doble, P; Finkelstein, DI; Bush, AI

Metal chaperones prevent zinc-mediated cognitive decline

Adlard, PA Parncutt, J Lal, V James, S Hare, D

Doble, P

Finkelstein, DI Bush, AI

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Publication Type:: Journal Article
Citation:: Neurobiology of Disease, 2015, 81 pp. 196 - 202
Issue Date:: 2015-09-01

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Field	Value	Language
dc.contributor.author	Adlard, PA	en_US
dc.contributor.author	Parncutt, J	en_US
dc.contributor.author	Lal, V	en_US
dc.contributor.author	James, S	en_US
dc.contributor.author	Hare, D https://orcid.org/0000-0002-5922-7643	en_US
dc.contributor.author	Doble, P https://orcid.org/0000-0002-8472-1301	en_US
dc.contributor.author	Finkelstein, DI	en_US
dc.contributor.author	Bush, AI	en_US
dc.date.available	2014-12-11	en_US
dc.date.issued	2015-09-01	en_US
dc.identifier.citation	Neurobiology of Disease, 2015, 81 pp. 196 - 202	en_US
dc.identifier.issn	0969-9961	en_US
dc.identifier.uri	http://hdl.handle.net/10453/35238
dc.description.abstract	© 2014 Elsevier Inc. 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 6 weeks) 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.	en_US
dc.relation.ispartof	Neurobiology of Disease	en_US
dc.relation.isbasedon	10.1016/j.nbd.2014.12.012	en_US
dc.subject.classification	Neurology & Neurosurgery	en_US
dc.subject.mesh	Hippocampus	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice, Knockout	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Disease Models, Animal	en_US
dc.subject.mesh	Zinc	en_US
dc.subject.mesh	Clioquinol	en_US
dc.subject.mesh	Carrier Proteins	en_US
dc.subject.mesh	Membrane Proteins	en_US
dc.subject.mesh	Patch-Clamp Techniques	en_US
dc.subject.mesh	Analysis of Variance	en_US
dc.subject.mesh	Escape Reaction	en_US
dc.subject.mesh	Maze Learning	en_US
dc.subject.mesh	Cognition Disorders	en_US
dc.subject.mesh	Gene Expression Regulation	en_US
dc.subject.mesh	Long-Term Potentiation	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Male	en_US
dc.subject.mesh	In Vitro Techniques	en_US
dc.subject.mesh	Membrane Transport Proteins	en_US
dc.title	Metal chaperones prevent zinc-mediated cognitive decline	en_US
dc.type	Journal Article
utslib.citation.volume	81	en_US
utslib.for	1103 Clinical Sciences	en_US
utslib.for	1109 Neurosciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CFS - Centre for Forensic Science
utslib.copyright.status	open_access
pubs.publication-status	Published	en_US
pubs.volume	81	en_US

Abstract:

© 2014 Elsevier Inc. 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 6 weeks) 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.

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http://hdl.handle.net/10453/35238