Metal chaperones prevent zinc-mediated cognitive decline
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....
Main Authors: | , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2015-09-01
|
Series: | Neurobiology of Disease |
Subjects: | |
Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996114003830 |
id |
doaj-30d4752944f04d0bbdce8e3c4e00e11b |
---|---|
record_format |
Article |
spelling |
doaj-30d4752944f04d0bbdce8e3c4e00e11b2021-03-22T12:42:22ZengElsevierNeurobiology of Disease1095-953X2015-09-0181196202Metal chaperones prevent zinc-mediated cognitive declinePaul A. Adlard0Jacqui Parncutt1Varsha Lal2Simon James3Dominic Hare4Philip Doble5David I. Finkelstein6Ashley I. Bush7The Florey Institute for Neuroscience and Mental Health and The University of Melbourne, Parkville, Victoria 3052, Australia; Corresponding author at: The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, Victoria 3052, Australia.The Mental Health Research Institute, Parkville, Victoria 3052, AustraliaThe Mental Health Research Institute, Parkville, Victoria 3052, AustraliaAustralian Synchrotron and the CSIRO Preventative Health Flagship, Clayton, Victoria 3168, AustraliaElemental Bio-imaging Centre, University of Technology Sydney, Broadway, New South Wales 2007, AustraliaElemental Bio-imaging Centre, University of Technology Sydney, Broadway, New South Wales 2007, AustraliaThe Florey Institute for Neuroscience and Mental Health and The University of Melbourne, Parkville, Victoria 3052, AustraliaThe Florey Institute for Neuroscience and Mental Health and The University of Melbourne, Parkville, Victoria 3052, AustraliaZinc 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.http://www.sciencedirect.com/science/article/pii/S0969996114003830ZincZnT3ClioquinolAnimal modelCognition |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Paul A. Adlard Jacqui Parncutt Varsha Lal Simon James Dominic Hare Philip Doble David I. Finkelstein Ashley I. Bush |
spellingShingle |
Paul A. Adlard Jacqui Parncutt Varsha Lal Simon James Dominic Hare Philip Doble David I. Finkelstein Ashley I. Bush Metal chaperones prevent zinc-mediated cognitive decline Neurobiology of Disease Zinc ZnT3 Clioquinol Animal model Cognition |
author_facet |
Paul A. Adlard Jacqui Parncutt Varsha Lal Simon James Dominic Hare Philip Doble David I. Finkelstein Ashley I. Bush |
author_sort |
Paul A. Adlard |
title |
Metal chaperones prevent zinc-mediated cognitive decline |
title_short |
Metal chaperones prevent zinc-mediated cognitive decline |
title_full |
Metal chaperones prevent zinc-mediated cognitive decline |
title_fullStr |
Metal chaperones prevent zinc-mediated cognitive decline |
title_full_unstemmed |
Metal chaperones prevent zinc-mediated cognitive decline |
title_sort |
metal chaperones prevent zinc-mediated cognitive decline |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2015-09-01 |
description |
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. |
topic |
Zinc ZnT3 Clioquinol Animal model Cognition |
url |
http://www.sciencedirect.com/science/article/pii/S0969996114003830 |
work_keys_str_mv |
AT paulaadlard metalchaperonespreventzincmediatedcognitivedecline AT jacquiparncutt metalchaperonespreventzincmediatedcognitivedecline AT varshalal metalchaperonespreventzincmediatedcognitivedecline AT simonjames metalchaperonespreventzincmediatedcognitivedecline AT dominichare metalchaperonespreventzincmediatedcognitivedecline AT philipdoble metalchaperonespreventzincmediatedcognitivedecline AT davidifinkelstein metalchaperonespreventzincmediatedcognitivedecline AT ashleyibush metalchaperonespreventzincmediatedcognitivedecline |
_version_ |
1724208213808644096 |