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 J Vassar, Berislav V. Zlokovic*

*Corresponding author for this work

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)279-293
Number of pages15
JournalJournal of Experimental Medicine
Volume216
Issue number2
DOIs
StatePublished - Feb 1 2019

Fingerprint

Protein C
Cerebrovascular Circulation
Alzheimer Disease
Stroke
Protein Precursors
Amyloid Plaques
Brain Diseases
Serine Proteases
Neuroprotective Agents
Neurodegenerative Diseases
Brain Injuries
Rodentia
Hippocampus
Anti-Inflammatory Agents
Neurons
Therapeutics

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Lazic, Divna ; Sagare, Abhay P. ; Nikolakopoulou, Angeliki M. ; Griffin, John H. ; Vassar, Robert J ; Zlokovic, Berislav V. / 3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice. In: Journal of Experimental Medicine. 2019 ; Vol. 216, No. 2. pp. 279-293.
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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.",
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3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice. / Lazic, Divna; Sagare, Abhay P.; Nikolakopoulou, Angeliki M.; Griffin, John H.; Vassar, Robert J; Zlokovic, Berislav V.

In: Journal of Experimental Medicine, Vol. 216, No. 2, 01.02.2019, p. 279-293.

Research output: Contribution to journalArticle

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