title: Heparan sulphate proteoglycan and the low-density lipoprotein receptor-related protein 1 constitute major pathways for neuronal amyloid-beta uptake.
abstract: Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder in which the aggregation and deposition of amyloid-β (Aβ) peptides in the brain are central to its pathogenesis. In healthy brains, Aβ is effectively metabolized with little accumulation. Cellular uptake and subsequent degradation of Aβ is one of the major pathways for its clearance in the brain. Increasing evidence has demonstrated significant roles for the low-density lipoprotein receptor-related protein 1 (LRP1) in the metabolism of Aβ in neurons, glia cells, and along the brain vasculatures. Heparan sulfate proteoglycan (HSPG) has also been implicated in several pathogenic features of AD, including its colocalization with amyloid plaques. Here, we demonstrate that HSPG and LRP1 cooperatively mediate cellular Aβ uptake. Fluorescence-activated cell sorter and confocal microscopy revealed that knockdown of LRP1 suppresses Aβ uptake, whereas overexpression of LRP1 enhances this process in neuronal cells. Heparin, which antagonizes HSPG, significantly inhibited cellular Aβ uptake. Importantly, treatment with heparin or heparinase blocked LRP1-mediated cellular uptake of Aβ. We further showed that HSPG is more important for the binding of Aβ to the cell surface than LRP1. The critical roles of HSPG in cellular Aβ binding and uptake were confirmed in Chinese hamster ovary cells genetically deficient in HSPG. We also showed that heparin and a neutralizing antibody to LRP1 suppressed Aβ uptake in primary neurons. Our findings demonstrate that LRP1 and HSPG function in a cooperative manner to mediate cellular Aβ uptake and define a major pathway through which Aβ gains entry to neuronal cells.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kanekiyo
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Liu
authors.forename: Lijuan
authors.initials: L
authors.lastname: Zhang
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D015153:Blotting, Western; D016466:CHO Cells; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004622:Embryo, Mammalian; D004705:Endocytosis / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D019812:Heparan Sulfate Proteoglycans / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006493:Heparin / Q000494:pharmacology; D007031:Hypothalamus / Q000166:cytology; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D018613:Microscopy, Confocal; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D011247:Pregnancy; D034741:RNA, Small Interfering; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D019812:Heparan Sulfate Proteoglycans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D006493:Heparin