Increased beta-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 Abeta, an important peptide in the etiology of Alzheimer's disease. This study was designed to investigate if Pb exposure altered Abeta 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 Abeta (200 pmol) was infused into the lateral ventricle and the plexus tissues were removed to quantify Abeta accumulation. Results revealed a significant increase in intracellular Abeta accumulation in the Pb-exposed animals compared to controls (p<0.001). When choroidal epithelial Z310 cells were treated with 10 microM Pb for 24 h and 48 h, Abeta (2 microM 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 Abeta 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 microM 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 Abeta, 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 Abeta in the choroid plexus; the effect appears to be mediated, at least in part, via suppression of LRP1 production following Pb exposure.
Behl
Mamta
M
School of Health Sciences, Purdue University, 550 Stadium Mall Drive, Room 1169, West Lafayette, IN 47907, USA.
Zhang
Yanshu
Y
Monnot
Andrew D
AD
Jiang
Wendy
W
Zheng
Wei
W
D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002831:Choroid Plexus / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D007274:Injections, Intraperitoneal; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000633:toxicity*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism*; D010477:Perfusion; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D015854:Up-Regulation
D016229:Amyloid beta-Peptides; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D009942:Organometallic Compounds; D010446:Peptide Fragments; D012333:RNA, Messenger; C078592:amyloid beta-protein (1-40); C008261:lead acetate