Iron (Fe) and copper (Cu) are essential to neuronal function; excess or deficiency of either is known to underlie the pathoetiology of several commonly known neurodegenerative disorders. This delicate balance of Fe and Cu in the central milieu is maintained by the brain barrier systems, i.e., the blood-brain barrier (BBB) between the blood and brain interstitial fluid and the blood- cerebrospinal fluid barrier (BCB) between the blood and cerebrospinal fluid (CSF). This review provides a concise description on the structural and functional characteristics of the brain barrier systems. Current understanding of Fe and Cu transport across the brain barriers is thoroughly examined, with major focuses on whether the BBB and BCB coordinate the direction of Fe and Cu fluxes between the blood and brain/CSF. In particular, the mechanism by which pertinent metal transporters in the barriers, such as the transferrin receptor (TfR), divalent metal transporter (DMT1), copper transporter (CTR1), ATP7A/B, and ferroportin (FPN), regulate metal movement across the barriers is explored. Finally, the detrimental consequences of dysfunctional metal transport by brain barriers, as a result of endogenous disorders or exogenous insults, are discussed. Understanding the regulation of Fe and Cu homeostasis in the central nervous system aids in the design of new drugs targeted on the regulatory proteins at the brain barriers for the treatment of metal’s deficiency or overload-related neurological diseases.
Rats that consume high-energy (HE) diets (i.e., diets high in saturated fats and sugar) show impaired hippocampal-dependent learning and memory (e.g., [1]). To further investigate this effect, we trained rats given restricted access to low-fat lab chow on hippocampal-dependent serial feature-negative (FN) and hippocampal-independent simple discrimination problems. When training was completed, Group Chow received ad libitum lab chow. The remaining rats received ad libitum HE diet. Performance on both discrimination problems was tested following 7, 14, 21 and 28 days of HE diet exposure. FN, but not simple discrimination, was abolished initially for all rats, and then re-emerged for Group Chow. For rats fed HE diet, those that weighed the least and had lowest amount of body fat (HE-diet resistant (HE-DR) rats), performed like Group Chow on both discrimination problems. However, HE diet-induced obese (HE-DIO) rats (i.e., rats that weighed the most weight and had the most body fat) performed like Group Chow on the simple discrimination problem, but were impaired throughout testing on the FN problem. Subsequent assessment of blood-brain barrier (BBB) permeability revealed that concentrations of an exogenously administered dye were elevated in the hippocampus, but not in the striatum or prefrontal cortex for HE-DIO rats relative to the HE-DR and Chow groups. The results indicate that the adverse consequences of HE diet on hippocampal-dependent cognitive functioning are associated with detrimental effects on the BBB and that both of these outcomes vary with sensitivity to HE diet-induced increases in weight and adiposity.
The choroid plexus, a barrier between the blood and cerebrospinal fluid (CSF), is known to accumulate lead (Pb) and also possibly function to maintain brain's homeostasis of Aβ, an important peptide in the etiology of Alzheimer's disease. This study was designed to investigate if Pb exposure altered Aβ levels in the blood-CSF barrier in the choroid plexus. Rats received ip injection of 27 mg Pb/kg. Twenty-four hr later, an FAM-labeled Aβ (200 pmol) was infused into the lateral ventricle and the plexus tissues removed to quantify Aβ accumulation. Results revealed a significant increase in intracellular Aβ accumulation in the Pb-exposed animals compared to controls (p<0.001). When choroidal epithelial Z310 cells were treated with 10 μM Pb for 24h and 48h, Aβ (2 μM in culture medium) accumulation was significantly increased by 1.5 fold (p<0.05) and 1.8 fold (p<0.05), respectively. To explore the mechanism, the effect of Pb on low-density lipoprotein receptor protein-1 (LRP1), an intracellular Aβ transport protein, was examined. Following acute Pb exposure with the aforementioned dose regimen, levels of LRP1 mRNA and proteins in the choroid plexus were decreased by 35 % (p<0.05) and 31.8% (p<0.05), respectively, in comparison to those of controls. In Z310 cells exposed to 10 μM Pb for 24 h and 48 h, a 33.1% and 33.4% decrease in the protein expression of LRP1 was observed (p<0.05), respectively. Knocking down LRP1 resulted in even more substantial increases of cellular accumulation of Aβ, from 31% in cells without knockdown to 72% in cells with LRP1 knockdown (p<0.05). Taken together, these results suggest that the acute exposure to Pb results in an increased accumulation of intracellular Aβ in the choroid plexus; the effect appears to be mediated, at least in part, via suppression of LRP1 production following Pb exposure.
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