title: A novel approach to rapidly prevent age-related cognitive decline.
abstract: 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.
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, Kenneth Myer Building, At Genetics Lane on Royal Parade, The University of Melbourne, Melbourne, Vic., 3010, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Adlard
authors.forename: Amelia
authors.initials: A
authors.lastname: Sedjahtera
authors.forename: Lydia
authors.initials: L
authors.lastname: Gunawan
authors.forename: Lisa
authors.initials: L
authors.lastname: Bray
authors.forename: Dominic
authors.initials: D
authors.lastname: Hare
authors.forename: Jessica
authors.initials: J
authors.lastname: Lear
authors.forename: Philip
authors.initials: P
authors.lastname: Doble
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
authors.forename: David I
authors.initials: DI
authors.lastname: Finkelstein
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cherny
mesh_terms: D000375:Aging / Q000187:drug effects / Q000473:pathology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002452:Cell Count; D007464:Clioquinol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D003072:Cognition Disorders / Q000188:drug therapy / Q000517:prevention & control*; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D018782:Maze Learning / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
chemical_list: D015415:Biomarkers; C531955:PBT2 compound; D017470:Receptors, Glutamate; C493465:Slc17a7 protein, mouse; D050598:Vesicular Glutamate Transport Protein 1; D018698:Glutamic Acid; D007464:Clioquinol; D054648:Protein Phosphatase 2; D015032:Zinc
keywords: PBT2; aging; anti-aging; cognition; zinc