Format

Send to

Choose Destination
J Exp Med. 2019 Feb 4;216(2):279-293. doi: 10.1084/jem.20181035. Epub 2019 Jan 15.

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

Author information

1
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA.
2
Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CA.
3
Department of Neurobiology, Institute for Biological Research, University of Belgrade, Belgrade, Republic of Serbia.
4
The Scripps Research Institute, La Jolla, CA.
5
Department of Medicine, University of California, San Diego, San Diego, CA.
6
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL.
7
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA zlokovic@usc.edu.

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.

PMID:
30647119
PMCID:
PMC6363429
[Available on 2019-08-04]
DOI:
10.1084/jem.20181035

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center