Lead-induced accumulation of beta-amyloid in the choroid plexus: role of low density lipoprotein receptor protein-1 and protein kinase C.
The choroid plexus (CP), constituting the blood-cerebrospinal fluid barrier, has the capacity to remove beta-amyloid (Abeta) from the cerebrospinal fluid. Our previous work indicates that exposure to lead (Pb) results in Abeta accumulation in the CP by decreasing the expression of low density lipoprotein receptor protein-1 (LRP1), a protein involved in the transport and clearance of Abeta. The current study was designed to explore the relationship between Abeta accumulation, protein kinase C (PKC) activity, and LRP1 status in the CP following Pb exposure. Confocal microscopy revealed that LRP1 was primarily localized in the cytosol of the CP in control rats and migrated distinctly towards the apical surface and the microvilli following acute Pb exposure (27 mg Pb/kg, i.p., 24h). Co-immunostaining revealed a co-localization of both PKC-delta and LRP1 in the cytosol of control rats, with a distinct relocalization of both towards the apical membrane following Pb exposure. Preincubation of the tissues with PKC-delta inhibitor rottlerin (2 microM) prior to Pb exposure in vitro, resulted in abolishing the Pb-induced relocalization of LRP1 to the apical surface. Importantly, a significant elevation in intracellular Abeta levels (p<0.01) was observed in the cytosol of the CP following Pb exposure, which was abolished following preincubation with rottlerin. In addition, rottlerin caused a relocalization of Abeta from the cytosol to the nucleus in both Pb-treated and control CP tissues. Finally, co-immunoprecipitation studies revealed a strong protein-protein interaction between LRP1 and PKC-delta in the CP. These studies suggest that Pb exposure disrupts Abeta homeostasis at the CP, owing partly to a Pb-induced relocalization of LRP1 via PKC-delta.
Behl
Mamta
M
School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA.
Zhang
Yanshu
Y
Shi
Yunzhou
Y
Cheng
Jixin
J
Du
Yansheng
Y
Zheng
Wei
W
D000098:Acetophenones / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D002460:Cell Line; D002831:Choroid Plexus / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D047468:Immunoprecipitation; D007424:Intracellular Fluid / Q000187:drug effects; D007854:Lead / Q000494:pharmacology*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D008297:Male; D018613:Microscopy, Confocal / Q000379:methods; D051745:Protein Kinase C-delta / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D000098:Acetophenones; D016229:Amyloid beta-Peptides; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D007854:Lead; C085746:rottlerin; D051745:Protein Kinase C-delta