Abstract
Manganese (Mn) is a trace nutrient necessary for life but becomes neurotoxic at high concentrations in the brain. The brain is a “privileged” organ that is separated from systemic blood circulation mainly by two barriers. Endothelial cells within the brain form tight junctions and act as the blood–brain barrier (BBB), which physically separates circulating blood from the brain parenchyma. Between the blood and the cerebrospinal fluid (CSF) is the choroid plexus (CP), which is a tissue that acts as the blood–CSF barrier (BCB). Pharmaceuticals, proteins, and metals in the systemic circulation are unable to reach the brain and spinal cord unless transported through either of the two brain barriers. The BBB and the BCB consist of tightly connected cells that fulfill the critical role of neuroprotection and control the exchange of materials between the brain environment and blood circulation. Many recent publications provide insights into Mn transport in vivo or in cell models. In this review, we will focus on the current research regarding Mn metabolism in the brain and discuss the potential roles of the BBB and BCB in maintaining brain Mn homeostasis.
Highlights
Manganese (Mn) is a trace nutrient necessary for life but becomes neurotoxic at high concentrations in the brain
A study of brain microvascular endothelial cells of human origin provides an analysis of time-dependent uptake of 54 Mn2+ that increased in the presence of a clathrin-dependent endocytosis inhibitor [67], demonstrating that the receptor-mediated endocytosis in the transferrin/transferrin receptor 1 (Tf/TfR1) and divalent metal transporter-1 (DMT1) pathway is not involved in Mn transport in this
In Belgrade rats that lack functional DMT1, brain Mn levels remained normal in the olfactory bulb, cortex, striatum, hippocampus, and cerebellum, while Fe levels decreased in all brain areas tested [68], suggesting that DMT1 is not required for Mn delivery into the brain
Summary
Manganese (Mn) is essential for life as it is necessary for the normal function of several enzymes, including the antioxidant enzyme Mn superoxide dismutase (MnSOD) [1] and the neurotransmitter synthesis enzyme glutamine synthetase [2]. In non-human chronic induced amyloid-beta precursorIn the brain of a patient with AD, there is a decrease of MnSOD activity and increased like protein 1 expression and increased the formation of amyloid plaques, which is one of oxidative stress [13,14]. Mice were administered daily MnCl2 doses of either 15 mg/kg or 60 mg/kg with increased amyloid-beta in the blood and decreased cognitive test scores in mice [18]. The study concludes that increased Mn exposure is correlated with increased These results suggest that brain Mn dyshomeostasis may be a factor in the development amyloid-beta in the blood and decreased cognitive test scores in mice [18]. These results of AD. that brain Mn dyshomeostasis may be a factor in the development of AD
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