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jem Home » 2019 Archive » 4 February » 216 (2): 279
Brief Definitive Report

3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice

Divna Lazic, Abhay P. Sagare, View ORCID ProfileAngeliki M. Nikolakopoulou, John H. Griffin, Robert Vassar, View ORCID ProfileBerislav V. Zlokovic  Correspondence email
Divna Lazic
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CADepartment of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CADepartment of Neurobiology, Institute for Biological Research, University of Belgrade, Belgrade, Republic of Serbia
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Abhay P. Sagare
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CADepartment of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CA
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Angeliki M. Nikolakopoulou
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CADepartment of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CA
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  • ORCID record for Angeliki M. Nikolakopoulou
John H. Griffin
The Scripps Research Institute, La Jolla, CADepartment of Medicine, University of California, San Diego, San Diego, CA
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Robert Vassar
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL
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Berislav V. Zlokovic
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CADepartment of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CA
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  • ORCID record for Berislav V. Zlokovic
  • For correspondence: zlokovic@usc.edu
DOI: 10.1084/jem.20181035 | Published January 15, 2019
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Abstract

3K3A-activated protein C (APC), a cell-signaling analogue of endogenous blood serine protease APC, exerts vasculoprotective, neuroprotective, and anti-inflammatory activities in rodent models of stroke, brain injury, and neurodegenerative disorders. 3K3A-APC is currently in development as a neuroprotectant in patients with ischemic stroke. Here, we report that 3K3A-APC inhibits BACE1 amyloidogenic pathway in a mouse model of Alzheimer’s disease (AD). We show that a 4-mo daily treatment of 3-mo-old 5XFAD mice with murine recombinant 3K3A-APC (100 µg/kg/d i.p.) prevents development of parenchymal and cerebrovascular amyloid-β (Aβ) deposits by 40–50%, which is mediated through NFκB–dependent transcriptional inhibition of BACE1, resulting in blockade of Aβ generation in neurons overexpressing human Aβ-precursor protein. Consistent with reduced Aβ deposition, 3K3A-APC normalized hippocampus-dependent behavioral deficits and cerebral blood flow responses, improved cerebrovascular integrity, and diminished neuroinflammatory responses. Our data suggest that 3K3A-APC holds potential as an effective anti-Aβ prevention therapy for early-stage AD.

  • Submitted: 1 June 2018
  • Revision received 5 October 2018
  • Accepted: 30 October 2018
Creative Commons logoCreative Commons logohttp://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/

This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

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© 2019 Lazic et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

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3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice
Divna Lazic, Abhay P. Sagare, Angeliki M. Nikolakopoulou, John H. Griffin, Robert Vassar, Berislav V. Zlokovic
Journal of Experimental Medicine Feb 2019, 216 (2) 279-293; DOI: 10.1084/jem.20181035

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The Journal of Experimental Medicine: 216 (2)

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February 4, 2019
Volume 216, No. 2

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