TY  - JOUR
AU  - Lazić, Divna
AU  - Sagare, Abhay P
AU  - Nikolakopoulou, Angeliki M
AU  - Griffin, John H
AU  - Vassar, Robert
AU  - Zloković, Berislav V
PY  - 2019
UR  - http://www.ncbi.nlm.nih.gov/pubmed/30647119
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3263
AB  - 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.
T2  - The Journal of Experimental Medicine
T1  - 3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice.
IS  - 2
VL  - 216
DO  - 10.1084/jem.20181035
SP  - 279
EP  - 293
ER  - 

@article{
author = "Lazić, Divna and Sagare, Abhay P and Nikolakopoulou, Angeliki M and Griffin, John H and Vassar, Robert and Zloković, Berislav V",
year = "2019",
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.",
journal = "The Journal of Experimental Medicine",
title = "3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice.",
number = "2",
volume = "216",
doi = "10.1084/jem.20181035",
pages = "279-293"
}

Lazić, D., Sagare, A. P., Nikolakopoulou, A. M., Griffin, J. H., Vassar, R.,& Zloković, B. V.. (2019). 3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice.. in The Journal of Experimental Medicine, 216(2), 279-293.
https://doi.org/10.1084/jem.20181035

Lazić D, Sagare AP, Nikolakopoulou AM, Griffin JH, Vassar R, Zloković BV. 3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice.. in The Journal of Experimental Medicine. 2019;216(2):279-293.
doi:10.1084/jem.20181035 .

Lazić, Divna, Sagare, Abhay P, Nikolakopoulou, Angeliki M, Griffin, John H, Vassar, Robert, Zloković, Berislav V, "3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice." in The Journal of Experimental Medicine, 216, no. 2 (2019):279-293,
https://doi.org/10.1084/jem.20181035 . .