A novel approach to rapidly prevent age-related cognitive decline

Authors

  • Paul A. Adlard,

    Corresponding author
    1. The Florey Institute of Neuroscience and Mental Health, Kenneth Myer Building, At Genetics Lane on Royal Parade, The University of Melbourne, Melbourne, Vic., Australia
    • Correspondence

      Associate Professor Paul Adlard, The Florey Institute of Neuroscience and Mental Health, Kenneth Myer Building, At Genetics Lane on Royal Parade, University of Melbourne, Melbourne, Vic. 3010, Australia. Tel.: +61 3 90356775; fax: +61 3 90353103; e-mail: padlard@unimelb.edu.au

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    • Equal last author.
  • Amelia Sedjahtera,

    1. The Florey Institute of Neuroscience and Mental Health, Kenneth Myer Building, At Genetics Lane on Royal Parade, The University of Melbourne, Melbourne, Vic., Australia
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  • Lydia Gunawan,

    1. The Florey Institute of Neuroscience and Mental Health, Kenneth Myer Building, At Genetics Lane on Royal Parade, The University of Melbourne, Melbourne, Vic., Australia
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  • Lisa Bray,

    1. The Florey Institute of Neuroscience and Mental Health, Kenneth Myer Building, At Genetics Lane on Royal Parade, The University of Melbourne, Melbourne, Vic., Australia
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  • Dominic Hare,

    1. Elemental Bio-imaging Facility, University of Technology, Sydney, NSW, Australia
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  • Jessica Lear,

    1. Elemental Bio-imaging Facility, University of Technology, Sydney, NSW, Australia
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  • Philip Doble,

    1. Elemental Bio-imaging Facility, University of Technology, Sydney, NSW, Australia
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  • Ashley I. Bush,

    1. The Florey Institute of Neuroscience and Mental Health, Kenneth Myer Building, At Genetics Lane on Royal Parade, The University of Melbourne, Melbourne, Vic., Australia
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  • David I. Finkelstein,

    1. The Florey Institute of Neuroscience and Mental Health, Kenneth Myer Building, At Genetics Lane on Royal Parade, The University of Melbourne, Melbourne, Vic., Australia
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  • Robert A. Cherny

    1. The Florey Institute of Neuroscience and Mental Health, Kenneth Myer Building, At Genetics Lane on Royal Parade, The University of Melbourne, Melbourne, Vic., Australia
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    • Equal last author.

Summary

The loss of cognitive function is a pervasive and often debilitating feature of the aging process for which there are no effective therapeutics. We hypothesized that a novel metal chaperone (PBT2; Prana Biotechnology, Parkville, Victoria, Australia) would enhance cognition in aged rodents. We show here that PBT2 rapidly improves the performance of aged C57Bl/6 mice in the Morris water maze, concomitant with increases in dendritic spine density, hippocampal neuron number and markers of neurogenesis. There were also increased levels of specific glutamate receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-d-aspartate), the glutamate transporter (VGLUT1) and glutamate itself. Markers of synaptic plasticity [calmodulin-dependent protein kinase II (CaMKII) and phosphorylated CaMKII, CREB, synaptophysin] were also increased following PBT2 treatment. We also demonstrate that PBT2 treatment results in a subregion-specific increase in hippocampal zinc, which is increasingly recognized as a potent neuromodulator. These data demonstrate that metal chaperones are a novel approach to the treatment of age-related cognitive decline.

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