Lead-induced accumulation of β-amyloid in the choroid plexus: Role of low density lipoprotein receptor protein-1 and protein kinase C |
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| Authors: | Mamta Behl Yanshu Zhang Yunzhou Shi Jixin Cheng Yansheng Du Wei Zheng |
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| Institution: | 1. School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA;2. School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA;3. Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;1. Department of Toxicology and Pharmacology, Veterinary School, Complutense University of Madrid, 28040 Madrid, Spain;2. Department of Toxicology and Legal Medicine, Medical School, Complutense University of Madrid, 28041 Madrid, Spain;3. Department of Pharmacology, Health Sciences School, Alfonso X University, 28691 Madrid, Spain;1. GH Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA;2. Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA;3. Taub Institute for Research on Alzheimer''s Disease and the Aging Brain, Columbia University, New York, NY, USA;4. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA;5. Purdue University School of Health Sciences, West Lafayette, IN, USA;1. Department of Internal Medicine, Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, South Korea;2. Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea;1. Department of Pediatrics, Division of Neonatology and Pediatric Hematology/Oncology, Chang Gung Memorial Hospital, Yunlin, Taiwan;2. Graduate Institute of Clinical Medical Science, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan;3. Department of Physiology and Pharmacology and Health Ageing Research Center, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan;4. Department of Anesthetics, Chang Gung Memorial Hospital at Linkuo and Chang Gung University, Kwei-San, Tao-Yuan, Taiwan;5. Research Center for Chinese Herbal Medicine and Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan;6. Translational Medicine Center, Taoyuan General Hospital, Ministry of Healthy and Welfare, Taoyuan, Taiwan;7. Department of Physical Therapy, China Medical University, Taichung, Taiwan;8. Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City, Taiwan;9. Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan;10. School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan;11. Department of Nursing, College of Nursing, Hungkuang University, Taichung, Taiwan |
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| Abstract: | The choroid plexus (CP), constituting the blood–cerebrospinal fluid barrier, has the capacity to remove beta-amyloid (Aβ) from the cerebrospinal fluid. Our previous work indicates that exposure to lead (Pb) results in Aβ 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 Aβ. The current study was designed to explore the relationship between Aβ 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., 24 h). Co-immunostaining revealed a co-localization of both PKC-δ 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-δ inhibitor rottlerin (2 μM) 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 Aβ 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 Aβ 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-δ in the CP. These studies suggest that Pb exposure disrupts Aβ homeostasis at the CP, owing partly to a Pb-induced relocalization of LRP1 via PKC-δ. |
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