Increased β-amyloid levels in the choroid plexus following lead exposure and the involvement of low-density lipoprotein receptor protein-1

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 A beta, an important peptide in the etiology of Alzheimer's disease. This study was designed to investigate if Pb exposure altered A beta levels at the blood-CSF barrier in the choroid plexus. Rats received ip injection of 27 mg Pb/kg. Twenty-four hours later, a FAM-labeled A beta (200 pmol) was infused into the lateral ventricle and the plexus tissues were removed to quantify A beta accumulation. Results revealed a significant increase in intracellular A beta accumulation in the Pb-exposed animals compared to controls (p<0.001). When choroidal epithelial Z310 cells were treated with 10 mu M Pb for 24 h and 48 h, A beta (2 mu M 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, we examined the effect of Pb on low-density lipoprotein receptor protein-1 (LRP1), an intracellular A beta transport protein. 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 mu M 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 A beta, 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 A beta in the choroid plexus: the effect appears to be mediated, at least in part, via Suppression of LRP1 production following Pb exposure. (C) 2009 Elsevier Inc. All rights reserved.