Glycoprotein 330/megalin: probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer disease amyloid beta at the blood-brain and blood-cerebrospinal fluid barriers
| Autor: | Jorge Ghiso, C. L. Martel, J G McComb, B. Frangione, G Zheng, Etsuro Matsubara, Berislav V. Zlokovic, R T McCluskey |
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| Rok vydání: | 1996 |
| Předmět: |
Male
Endothelium Amyloid Amyloid beta Blotting Western Guinea Pigs Molecular Sequence Data Heymann Nephritis Antigenic Complex Biology Blood–brain barrier urologic and male genital diseases Antibodies Capillary Permeability Iodine Radioisotopes Cerebrospinal fluid medicine Animals Amino Acid Sequence Receptor Glycoproteins Multidisciplinary Amyloid beta-Peptides Membrane Glycoproteins Microcirculation Brain Molecular biology Epithelium Peptide Fragments Blot Kinetics medicine.anatomical_structure Clusterin Biochemistry Receptors LDL Blood-Brain Barrier Cerebrovascular Circulation Choroid Plexus biology.protein Female Endothelium Vascular Molecular Chaperones Research Article |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 93(9) |
| ISSN: | 0027-8424 |
| Popis: | A soluble form of Alzheimer disease amyloid beta-protein (sA beta) is transported in the blood and cerebrospinal fluid mainly complexed with apolipoprotein J (apoJ). Using a well-characterized in situ perfused guinea pig brain model, we recently obtained preliminary evidence that apoJ facilitates transport of sA beta (1-40)-apoJ complexes across the blood-brain barrier and the blood-cerebrospinal fluid barrier, but the mechanisms remain poorly understood. In the present study, we examined the transport process in greater detail and investigated the possible role of glycoprotein 330 (gp330)/megalin, a receptor for multiple ligands, including apoJ. High-affinity transport systems with a Km of 0.2 and 0.5 nM were demonstrated for apoJ at the blood-brain barrier and the choroid epithelium in vivo, suggesting a specific receptor-mediated mechanism. The sA beta (1-40)-apoJ complex shared the same transport mechanism and exhibited 2.4- to 10.2-fold higher affinity than apoJ itself. Binding to microvessels, transport into brain parenchyma, and choroidal uptake of both apoJ and sA beta (1-40)-apoJ complexes were markedly inhibited (74-99%) in the presence of a monoclonal antibody to gp330/megalin and were virtually abolished by perfusion with the receptor-associated protein, which blocks binding of all known ligands to gp330. Western blot analysis of cerebral microvessels with the monoclonal antibody to gp330 revealed a protein with a mass identical to that in extracts of kidney membranes enriched with gp330/megalin, but in much lower concentration. The findings suggest that gp330/megalin mediates cellular uptake and transport of apoJ and sA beta (1-40)-apoJ complex at the cerebral vascular endothelium and choroid epithelium. |
| Databáze: | OpenAIRE |
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