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Clearance of amyloid-β by circulating lipoprotein receptors

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Abstract

Low-density lipoprotein receptor–related protein-1 (LRP) on brain capillaries clears amyloid β-peptide (Aβ) from brain. Here, we show that soluble circulating LRP (sLRP) provides key endogenous peripheral 'sink' activity for Aβ in humans. Recombinant LRP cluster IV (LRP-IV) bound Aβ in plasma in mice and Alzheimer's disease–affected humans with compromised sLRP-mediated Aβ binding, and reduced Aβ-related pathology and dysfunction in a mouse model of Alzheimer disease, suggesting that LRP-IV can effectively replace native sLRP and clear Aβ.

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Figure 1: LRP-IV clears mouse endogenous brain Aβ, improves function and clears human brain Aβ in APP+/sw mice.
Figure 2: LRP-IV controls Aβ pathology in APP+/sw mice and sLRP and LRP-IV regulate peripheral Aβ in Alzheimer's disease.

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Acknowledgements

This work was supported by US National Institutes of Health (NIH) grants R37 AG023084 and R37 NS34467 to B.V.Z. and Washington University St. Louis Alzheimer's Disease Research Center grant P50 AG05681.

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Author notes

  1. Abhay Sagare, Rashid Deane and Robert D Bell: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Frank P. Smith Laboratory for Neuroscience and Neurosurgical Research, University of Rochester Medical School, Rochester, 14642, New York, USA

    Abhay Sagare, Rashid Deane, Robert D Bell, Bradley Johnson, Katie Hamm, Andrew Marky, Zhenhua Wu, David Perlmutter, Mireia Coma, Zhihui Zhong & Berislav V Zlokovic

  2. Department of Hematology, Laboratory for Thrombosis and Haemostasis, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands

    Ronan Pendu & Peter J Lenting

  3. Department of Environmental Medicine, Neurobehavioral Facility Laboratory, University of Rochester Medical School, Rochester, New York, USA

    Troy Zarcone

  4. Department of Psychiatry, B8134, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Alison Goate & Kevin Mayo

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  1. Abhay Sagare
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  2. Rashid Deane
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  9. Zhenhua Wu
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  15. Zhihui Zhong
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  16. Berislav V Zlokovic
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Contributions

A.S. conducted and performed in vivo studies in wild-type and APP+/sw (APPsw+/−) mice. R.D. conducted and performed pharmacokinetic and cerebral blood flow studies and work on the human study protocol. R.D.B. conducted and performed in vitro ligand binding assays and Aβ immunostaining studies. B.J. performed the oxidized sLRP assay and sLRP ELISA assay. K.H. performed in vivo studies in wild-type mice. R.P. purified recombinant LRP-IV. A.M. performed cholesterol and apoE assays. P.J.L. supervised R.P. and provided LRP-IV. Z.W. conducted and performed memory tests in mice. T.Z. performed approach and operant learning test in mice. D.P. performed active tPA and pro-MMP-9 assays. A.G. and K.M. performed LRP polymorphism studies. M.C. performed immunoprecipitation of oxidized proteins. Z.Z. performed Prussian blue staining. B.V.Z. designed the entire study, supervised all portions of the study and wrote the manuscript.

Corresponding author

Correspondence to Berislav V Zlokovic.

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Competing interests

B.V.Z. is Scientific Founder and Program Director of Socratech LLC, a startup biotechnology company with a mission to develop therapeutics for Alzheimer's disease, stroke and other neurodegenerative disorders, and owns shares in the company. He does not receive direct financial compensation from Socratech LLC.

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Supplementary Text and Figures

Supplementary Figs. 1–7, Supplementary Table 1 and Methods (PDF 8244 kb)

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Sagare, A., Deane, R., Bell, R. et al. Clearance of amyloid-β by circulating lipoprotein receptors. Nat Med 13, 1029–1031 (2007). https://doi.org/10.1038/nm1635

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  • DOI: https://doi.org/10.1038/nm1635

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