title: Identification of Cerebral Metal Ion Imbalance in the Brain of AgingOctodon degus.
abstract: The accumulation of redox-active transition metals in the brain and metal dyshomeostasis are thought to be associated with the etiology and pathogenesis of several neurodegenerative diseases, and Alzheimer's disease (AD) in particular. As well, distinct biometal imaging and role of metal uptake transporters are central to understanding AD pathogenesis and aging but remain elusive, due inappropriate detection methods. We therefore hypothesized thatOctodon degusdevelop neuropathological abnormalities in the distribution of redox active biometals, and this effect may be due to alterations in the expression of lysosomal protein, major Fe/Cu transporters, and selected Zn transporters (ZnTs and ZIPs). Herein, we report the distribution profile of biometals in the aged brain of the endemic Chilean rodentO. degus-a natural model to investigate the role of metals on the onset and progression of AD. Using laser ablation inductively coupled plasma mass spectrometry, our quantitative images of biometals (Fe, Ca, Zn, Cu, and Al) appear significantly elevated in the agedO. degusand show an age-dependent rise. The metals Fe, Ca, Zn, and Cu were specifically enriched in the cortex and hippocampus, which are the regions where amyloid plaques, tau phosphorylation and glial alterations are most commonly reported, whilst Al was enriched in the hippocampus alone. Using whole brain extracts, age-related deregulation of metal trafficking pathways was also observed inO. degus. More specifically, we observed impaired lysosomal function, demonstrated by increased cathepsin D protein expression. An age-related reduction in the expression of subunit B2 of V-ATPase, and significant increases in amyloid beta peptide 42 (Aβ42), and the metal transporter ATP13a2 were also observed. Although the protein expression levels of the zinc transporters, ZnT (1,3,4,6, and 7), and ZIP7,8 and ZIP14 increased in the brain of agedO. degus, ZnT10, decreased. Although no significant age-related change was observed for the major iron/copper regulator IRP2, we did find a significant increase in the expression of DMT1, a major transporter of divalent metal species, 5'-aminolevulinate synthase 2 (ALAS2), and the proto-oncogene, FOS. Collectively, our data indicate that transition metals may be enriched with age in the brains ofO. degus, and metal dyshomeostasis in specific brain regions is age-related.
authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales Sydney, NSW, Australia.
authors.forename: Nady
authors.initials: N
authors.lastname: Braidy
authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South WalesSydney, NSW, Australia; Mark Wainwright Analytical Centre, University of New South WalesSydney, NSW, Australia; School of Medical Sciences, Faculty of Medicine, University of New South WalesSydney, NSW, Australia.
authors.forename: Anne
authors.initials: A
authors.lastname: Poljak
authors.affiliation: Mark Wainwright Analytical Centre, University of New South Wales Sydney, NSW, Australia.
authors.forename: Chris
authors.initials: C
authors.lastname: Marjo
authors.affiliation: Mark Wainwright Analytical Centre, University of New South Wales Sydney, NSW, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Rutlidge
authors.affiliation: Mark Wainwright Analytical Centre, University of New South Wales Sydney, NSW, Australia.
authors.forename: Anne
authors.initials: A
authors.lastname: Rich
authors.affiliation: School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales Sydney, NSW, Australia.
authors.forename: Bat-Erdene
authors.initials: BE
authors.lastname: Jugder
authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales Sydney, NSW, Australia.
authors.forename: Tharusha
authors.initials: T
authors.lastname: Jayasena
authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South WalesSydney, NSW, Australia; Centre for Ageing and Regeneration, Faculty of Biological Sciences, Pontifical Catholic University of ChileSantiago, Chile.
authors.forename: Nibaldo C
authors.initials: NC
authors.lastname: Inestrosa
authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South WalesSydney, NSW, Australia; Neuropsychiatric Institute, Euroa Centre, Prince of Wales HospitalSydney, NSW, Australia.
authors.forename: Perminder S
authors.initials: PS
authors.lastname: Sachdev
keywords: Alzheimer’s disease; LA-ICPMS; Octodon degus; bioimaging; metals