Metal Ion Physiopathology in Neurodegenerative Disorders

Abstract

Metal dyshomeostasis in the brain (BMD) has often been proposed as a possible cause for several neurodegenerative disorders (NDs). Nevertheless, the precise nature of the biochemical mechanisms of metal involvement in NDs is still largely unknown. Mounting evidence suggests that normal aging itself is characterized by, among other features, a significant degree of metal ion dysmetabolism in the brain. This is probably the result of a progressive deterioration of the metal regulatory systems and, at least in some cases, of life-long metal exposure and brain accumulation. Although alterations of metal metabolism do occur to some extent in normal aging, they appear to be highly enhanced under various neuropathological conditions, causing increased oxidative stress and favoring abnormal metal-protein interactions. Intriguingly, despite the fact that most common NDs have a distinct etiological basis, they share striking similarities as they are all characterized by a documented brain metal impairment. This review will primarily focus on the alterations of metal homeostasis that are observed in normal aging and in Alzheimer's disease. We also present a brief survey on BMD in other NDs (Amyotrophic Lateral Sclerosis, Parkinson's, and Prion Protein disease) in order to highlight what represents the most reliable evidence supporting a crucial involvement of metals in neurodegeneration. The opportunities for metal-targeted pharmacological strategies in the major NDs are briefly outlined as well.

Genetic variability at the PARK16 locus

“…Brain metal dyshomeostasis has often been speculated as a cause of neurodegeneration; nevertheless, the precise nature of its biochemical mechanisms underlying neurodegeneration is still vague. 21,22 Although no association between the PARK16 locus and PD was identified in a GWAS meta-analysis, 14 analyses of PARK16-associated SNPs within the HapMap data revealed marked differences in the minor allelic frequencies between populations, thus affecting analytic power (Table 3). Similarly, population differences at the BST1 and MAPT loci were recently reported, 12,13 and the haplotype H2 of MAPT reported to be almost exclusively of Caucasian origin is low in all populations.…”

Copper(I) and Copper(II) Inhibit Aβ Peptides Proteolysis by Insulin‐Degrading Enzyme Differently: Implications for Metallostasis Alteration in Alzheimer’s Disease

“…[3] Alteration of metal homeostasis (metallostasis) has also been advocated as a key feature in the development and progression of AD, even though a detailed understanding of the molecular mechanisms associating metal alteration and neurodegeneration is still far from being understood. [4] This is due not only to the experimental difficulties to obtain unambiguous analytical data on AD brain that allow the assessment of metallostasis alteration but also to the complex Abstract: Accumulation of neurotoxic amyloid-b peptide (Ab) and alteration of metal homeostasis (metallostasis) in the brain are two main factors that have been very often associated with neurodegenerative diseases, such as Alzheimers disease (AD). Ab is constantly produced from the amyloid-A C H T U N G T R E N N U N G precursor-protein APP precursor and immediately catabolized under normal conditions, whereas dysmetabolism of Ab and/or metal ions seems to lead to a pathological deposition.…”

“…The solution was then filtered by using a medium porosity frit, and the filtrate concentrated by vacuum tõ 20 mL. Diethyl ether (~25 mL) was added slowly to the filtrate and the solution cooled overnight to yield white needle crystals of [Cu 4 ) that was used as the source of copper(I) ion in the enzymatic assay. Because of the isotopic composition, molecular species are detected in the mass spectra as clusters of peaks; to simplify their assignments, the reported calculated values refer to monoisotopic m/z.…”

Disruption of Neurosynaptic Physiology and Neuron Network Dysfunction in Brain Disorders: An Environmental and Occupational Health Perspective

“…Perturbed ER calcium homeostasis contributes to neuronal dysfunction and degeneration [130]. Although each pollutant has its own mechanism of toxicity, several air pollutants like, ozone, sulfer dioxide, volatile organic compounds and PM are oxidants, capable of directly acting on cellular components and disrupt physiological function [131][132][133]. Animals exposed to high levels of air pollution, such as fine and ultrafine particulate matter, lipopolysaccherides associated with PM, ozone and dissel engine exaust, show an increase of proinflammatory cytokines in brain tissue [134][135][136][137].…”