title: Apolipoprotein E lipoprotein particles inhibit amyloid-β uptake through cell surface heparan sulphate proteoglycan.
abstract: The accumulation, aggregation and deposition of amyloid-β (Aβ) peptides in the brain are central to the pathogenesis of Alzheimer's disease (AD). Alzheimer's disease risk increases significantly in individuals carrying one or two copies of APOE ε4 allele compared to individuals with an ε3/ε3 genotype. Growing evidence has demonstrated that apolipoprotein E (apoE) strongly influences AD pathogenesis by controlling Aβ aggregation and metabolism. Heparan sulphate proteoglycans (HSPGs) are abundant cell surface molecules that bind to both apoE and Aβ. HSPGs have been associated with Aβ aggregation and deposition. Although several lines of research have shown that apoE influences Aβ clearance in the brain, it is not clear how apoE influences HSPG-mediated cellular uptake of Aβ.
  
  
  
  In this study, we show that apoE lipoprotein particles from conditioned media of immortalized astrocytes isolated from human APOE-targeted replacement (TR) mice significantly suppress cellular Aβ42 and Aβ40 uptake through cell surface HSPG. ApoE3 and apoE4 particles have similar binding affinity to heparin, while apoE4 particles are likely hypolipidated compared to apoE particles. We also found that the apoE particles antagonize Aβ binding to cell surface, and inhibited Aβ uptake in a concentration-dependent manner in Chinese hamster ovary (CHO) cells. While the effect was not apoE isoform-dependent, the suppressive effect of apoE particles on Aβ uptake was not observed in HSPG-deficient CHO cells. We further demonstrated that apoE particles reduced the internalization of Aβ in mouse primary neurons, an effect that is eliminated by the presence of heparin.
  
  
  
  Taken together, our findings indicate that apoE particles irrespective of isoform inhibit HSPG-dependent cellular Aβ uptake. Modulating the ability of apoE particles to affect Aβ cellular uptake may hold promises for developing new strategies for AD therapy.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.|Department of Neurology, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Atagi
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Henrietta M
authors.initials: HM
authors.lastname: Nielsen
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.|Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China.
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Liu
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.|Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China.
authors.forename: Honghua
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Shinohara
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. kanekiyo.takahisa@mayo.edu.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kanekiyo
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. bu.guojun@mayo.edu.|Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China. bu.guojun@mayo.edu.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D002469:Cell Separation; D002850:Chromatography, Gel; D006224:Cricetinae; D003412:Cricetulus; D004797:Enzyme-Linked Immunosorbent Assay; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D019812:Heparan Sulfate Proteoglycans; D008565:Membrane Proteins
keywords: Alzheimer’s disease; Aβ; Cellular uptake; HSPG; apoE