The role of zinc, copper, manganese and iron in neurodegenerative diseases

• Published in: Neurotoxicology (Park Forest South) 2019-09, Vol.74, p.230-241
• Main Authors: Mezzaroba, Leda, Alfieri, Daniela Frizon, Colado Simão, Andrea Name, Vissoci Reiche, Edna Maria
• Format: Article
• Language: English
• Subjects: Accumulation; Activator protein 1; Adenosine triphosphate; Agglomeration; Alzheimer disease; Alzheimer's disease; Animals; Apoptosis; ATP; Axonal transport; Blood-brain barrier; Cell death; Central nervous system; Copper; Copper - toxicity; Disruption; Down-regulation; Essentials metals; Geographical variations; Heavy metals; Helper cells; Homeostasis; Humans; Inclusions; Inflammation; Iron; Iron - toxicity; Levels; Lymphocytes T; Macrophages; Manganese; Manganese - toxicity; Manganese Poisoning - pathology; Manganese Poisoning - psychology; Metals; Movement disorders; Multiple sclerosis; Neostriatum; Neurodegeneration; Neurodegenerative diseases; Neurodegenerative Diseases - chemically induced; Neurodegenerative Diseases - pathology; Neurodegenerative Diseases - psychology; Neurotoxicity; Oxidative stress; Parkinson disease; Parkinson's disease; Pathogenesis; Proteins; Receptors; Senile plaques; Thalamus; Zinc; Zinc - toxicity; β-Amyloid
• ISSN: 0161-813X; 1872-9711
• DOI: 10.1016/j.neuro.2019.07.007

•Excessive metal levels induce neurodegeneration by oxidative stress, disrupting mitochondrial function, and cell death.•The role of zinc (Zn), copper (Cu), manganese (Mn), and iron (Fe) in Alzheimer disease, Parkinson disease, and multiple sclerosis was reviewed.•Zn deficiency and high levels of Cu, Mn, and Fe participate in the activation of nuclear factor kappa B and induce inflammatory and oxidative stress.•High levels of Cu, Mn and Fe participate in the formation of intracellular inclusions, called Lewy Body, a marker of Parkinson disease.•Zn deficiency induces an imbalance of Th1/Th2 cells and a failure of Th17 downregulation, contributing to multiple sclerosis pathogenesis. Metals are involved in different pathophysiological mechanisms associated with neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD) and multiple sclerosis (MS). The aim of this study was to review the effects of the essential metals zinc (Zn), copper (Cu), manganese (Mn) and iron (Fe) on the central nervous system (CNS), as well as the mechanisms involved in their neurotoxicity. Low levels of Zn as well as high levels of Cu, Mn, and Fe participate in the activation of signaling pathways of the inflammatory, oxidative and nitrosative stress (IO&NS) response, including nuclear factor kappa B and activator protein-1. The imbalance of these metals impairs the structural, regulatory, and catalytic functions of different enzymes, proteins, receptors, and transporters. Neurodegeneration occurs via association of metals with proteins and subsequent induction of aggregate formation creating a vicious cycle by disrupting mitochondrial function, which depletes adenosine triphosphate and induces IO&NS, cell death by apoptotic and/or necrotic mechanisms. In AD, at low levels, Zn suppresses β-amyloid-induced neurotoxicity by selectively precipitating aggregation intermediates; however, at high levels, the binding of Zn to β-amyloid may enhance formation of fibrillar β-amyloid aggregation, leading to neurodegeneration. High levels of Cu, Mn and Fe participate in the formation α-synuclein aggregates in intracellular inclusions, called Lewy Body, that result in synaptic dysfunction and interruption of axonal transport. In PD, there is focal accumulation of Fe in the substantia nigra, while in AD a diffuse accumulation of Fe occurs in various regions, such as cortex and hippocampus, with Fe marginally increased in the senile plaques. Zn deficiency induces