Abstract
Biometal dyshomeostasis and toxic metal accumulation are common features in many neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease, and Huntington’s disease. The neurotoxic effects of metal imbalance are generally associated with reduced enzymatic activities, elevated protein aggregation and oxidative stress in the central nervous system, in which a cascade of events lead to cell death and neurodegeneration. Although the links between biometal imbalance and neurodegenerative disorders remain elusive, a major class of endogenous proteins involved in metal transport has been receiving increasing attention over recent decades. The abnormal expression of these proteins has been linked to biometal imbalance and to the pathogenesis of AD. Here, we present a brief overview of the physiological roles of biometals including iron, zinc, copper, manganese, magnesium and calcium, and provide a detailed description of their transporters and their synergistic involvement in the development of AD. In addition, we also review the published data relating to neurotoxic metals in AD, including aluminum, lead, cadmium, and mercury.
Highlights
Alzheimer’s disease (AD) is the most common neurodegeneration disorder linked with dementia in the elderly (Todd et al, 2013)
Cd can cross over the blood–brain barrier (BBB) and long-term exposure to Cd causes its accumulation in the brain which can activate various signaling cascades to stimulate inflammation, oxidative stress, and lead to neuronal death, which eventually influences olfaction, attention, and cognitive function (Figueiredo-Pereira et al, 1998; Wang and Du, 2013)
Transport Fe2+, Cu2+, Mn2+ into cytosol Tf/transferrin receptor (TfR) is endocytosed, by which Fe3+ is reduced to Fe2+ Lf/LfR complex facilitate Fe3+ uptake Mediate Fe2+, Mn2+ export out of cells Transport Fe3+ across the BBB Cell surface Cu+ uptake Cellular Cu+ exporter Cellular Cu+ exporter Export Zn2+ from neurons Zn2+ uptake Expressed in astrocytes for Zn2+ uptake Expressed in neurons for Zn2+ uptake Mn2+ influx into the cytosol Mn2+ influx into the cytosol Transport Mn2+ into the lysosomes Mediate efflux of Mn2+ Transport Mn2+ into the Golgi Mediate Mg2+ influx Mg2+ entry channel Mediate Na+-dependent Mg2+ extrusion Control Ca2+ influx under electrical activity Extrude Ca2+ from the cytoplasm in exchange for Na+ entry Mediate Ca2+ influx Mediate Ca2+ influx Mediate Ca2+ influx
Summary
Alzheimer’s disease (AD) is the most common neurodegeneration disorder linked with dementia in the elderly (Todd et al, 2013). Metal Ions and Alzheimer’s Disease role in the aggregation and metabolism of Aβ and tau protein. The pathophysiological roles of metal imbalance in the brain have been recently described in several outstanding reviews (Chin-Chan et al, 2015a; Zhang et al, 2016). Since biometals cannot passively pass through the blood–brain barrier (BBB), the described metal imbalance in the AD brain cannot merely be related to the increased or decreased exposure to metals, but rather to a more primary distribution of intracellular ions in a confusing way. The dysregulation of these metal transport-related proteins in the pathogenesis of AD has been extensively studied. In this review, we describe the recent advances in our understanding of the role of biometals in the molecular mechanisms underlying AD. We present evidence of molecular links between toxic metals and AD
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