Receptor-associated protein interacts with amyloid-beta peptide and promotes its cellular uptake.
Brain amyloid-beta (Abeta) peptide accumulation and aggregation are critical events in the pathogenesis of Alzheimer disease. Increasing evidence has demonstrated that LRP1 is involved in Alzheimer disease pathogenesis. The physiological ligands of LRP1, including apoE, play significant roles in the cellular clearance of Abeta. The receptor-associated protein (RAP) is a specialized chaperone for members of the low density lipoprotein receptor family. RAP shares structural and receptor-binding properties with apoE. Here, we show that RAP binds to both Abeta40 and Abeta42 in a concentration-dependent manner and forms complexes with them. Fluorescence-activated cell sorter analysis showed that RAP significantly enhances the cellular internalization of Abeta in different cell types, including brain vascular smooth muscle, neuroblastoma, glioblastoma, and Chinese hamster ovary cells. This effect of RAP was confirmed by fluorescence microscopy and enzyme-linked immunosorbent assay. RAP binds to both LRP1 and heparin; however, the ability of RAP to enhance Abeta cellular uptake was blocked by heparin and heparinase treatment but not by LRP1 deficiency. Furthermore, the effects of RAP were significantly decreased in heparan sulfate proteoglycan-deficient Chinese hamster ovary cells. Our findings reveal that RAP is a novel Abeta-binding protein that promotes cellular internalization of Abeta.
Kanekiyo
Takahisa
T
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Bu
Guojun
G
D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000166:cytology; D016466:CHO Cells; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004705:Endocytosis; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D026563:LDL-Receptor Related Protein-Associated Protein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D026563:LDL-Receptor Related Protein-Associated Protein; D011973:Receptors, LDL; D006493:Heparin