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 that Octodon degus develop 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 rodent O. 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 aged O. degus and 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 in O. 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 aged O. 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 of O. degus, and metal dyshomeostasis in specific brain regions is age-related.
Highlights
Alzheimer’s disease (AD) is the most common progressive agerelated neurodegenerative disorder, characterized by debilitating effects on brain function, such as memory loss and decline in cognitive abilities resulting in loss of independent functioning (Teri et al, 1989; Baddeley et al, 1991; Terry et al, 1991)
No reliable “natural” model of AD is available, and current AD research largely uses transgenic models, which have a number of limitations, including the fact that they do not recapitulate the morphological and temporal patterns observed in clinical AD in humans (Braidy et al, 2012, 2015)
Data on molecular mechanisms and drug efficacy testing using these genetically modified models should be interpreted with care, as many previous discoveries made in transgenic models have been lost in human translation (Braidy et al, 2012, 2015)
Summary
Alzheimer’s disease (AD) is the most common progressive agerelated neurodegenerative disorder, characterized by debilitating effects on brain function, such as memory loss and decline in cognitive abilities resulting in loss of independent functioning (Teri et al, 1989; Baddeley et al, 1991; Terry et al, 1991). It has been demonstrated that Cu, Fe, and Zn are associated with the metabolism and functional roles of Aβ and amyloid precursor protein (APP; Smith et al, 2007). This has led to the hypothesis that abnormal biometal deposition may play an important role in the pathobiology of AD, and metal chelation may represent an important therapeutic strategy to prevent the onset or slow down the progression of AD (Bush, 2003; Faux et al, 2010; Bonda et al, 2011; Braidy et al, 2014).
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