TY - JOUR
T1 - 3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice
AU - Lazic, Divna
AU - Sagare, Abhay P.
AU - Nikolakopoulou, Angeliki M.
AU - Griffin, John H.
AU - Vassar, Robert
AU - Zlokovic, Berislav V.
N1 - Funding Information:
This research was supported in part by National Institutes of Health grants NS090904 (B.V. Zlokovic) and HL052246 (J.H. Griffin) for development of APC variants and PAR1 mimetic peptides for stroke and by University of Southern California start-up funds to B.V. Zlokovic.
Publisher Copyright:
© 2019 Lazic et al.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85060934988&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85060934988&partnerID=8YFLogxK
U2 - 10.1084/jem.20181035
DO - 10.1084/jem.20181035
M3 - Article
C2 - 30647119
AN - SCOPUS:85060934988
VL - 216
SP - 279
EP - 293
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 2
ER -