| First Author | Lazic D | Year | 2019 |
| Journal | J Exp Med | Volume | 216 |
| Issue | 2 | Pages | 279-293 |
| PubMed ID | 30647119 | Mgi Jnum | J:273215 |
| Mgi Id | MGI:6284603 | Doi | 10.1084/jem.20181035 |
| Citation | Lazic D, et al. (2019) 3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice. J Exp Med 216(2):279-293 |
| abstractText | 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 microg/kg/d i.p.) prevents development of parenchymal and cerebrovascular amyloid-beta (Abeta) deposits by 40-50%, which is mediated through NFkappaB-dependent transcriptional inhibition of BACE1, resulting in blockade of Abeta generation in neurons overexpressing human Abeta-precursor protein. Consistent with reduced Abeta 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-Abeta prevention therapy for early-stage AD. |
