Apolipoprotein e lipoprotein particles inhibit amyloid-β uptake through cell surface heparan sulphate proteoglycan

Yuan Fu, Jing Zhao, Yuka Atagi, Henrietta M. Nielsen, Chia-Chen Liu, Honghua Zheng, Mitsuru Shinohara, Takahisa Kanekiyo, Guojun D Bu

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Article number99
JournalMolecular Neurodegeneration
Volume11
Issue number1
DOIs
StatePublished - May 5 2016

Fingerprint

Heparan Sulfate Proteoglycans
Apolipoproteins
Apolipoproteins E
Amyloid
Lipoproteins
Alzheimer Disease
Apolipoprotein E4
Cricetulus
Heparin
Ovary
Protein Isoforms
Apolipoprotein E3
Apolipoproteins A
Aptitude
Brain
Conditioned Culture Medium
Astrocytes

Keywords

  • Alzheimer's disease
  • apoE
  • Cellular uptake
  • HSPG

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Clinical Neurology
  • Molecular Biology

Cite this

Apolipoprotein e lipoprotein particles inhibit amyloid-β uptake through cell surface heparan sulphate proteoglycan. / Fu, Yuan; Zhao, Jing; Atagi, Yuka; Nielsen, Henrietta M.; Liu, Chia-Chen; Zheng, Honghua; Shinohara, Mitsuru; Kanekiyo, Takahisa; Bu, Guojun D.

In: Molecular Neurodegeneration, Vol. 11, No. 1, 99, 05.05.2016.

Research output: Contribution to journalArticle

Fu, Yuan ; Zhao, Jing ; Atagi, Yuka ; Nielsen, Henrietta M. ; Liu, Chia-Chen ; Zheng, Honghua ; Shinohara, Mitsuru ; Kanekiyo, Takahisa ; Bu, Guojun D. / Apolipoprotein e lipoprotein particles inhibit amyloid-β uptake through cell surface heparan sulphate proteoglycan. In: Molecular Neurodegeneration. 2016 ; Vol. 11, No. 1.
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AU - Fu, Yuan

AU - Zhao, Jing

AU - Atagi, Yuka

AU - Nielsen, Henrietta M.

AU - Liu, Chia-Chen

AU - Zheng, Honghua

AU - Shinohara, Mitsuru

AU - Kanekiyo, Takahisa

AU - Bu, Guojun D

PY - 2016/5/5

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N2 - Background: 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. Results: 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. Conclusions: 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.

AB - Background: 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. Results: 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. Conclusions: 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.

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