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

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-? (A?) deposits by 40-50%, which is mediated through NF?B-dependent transcriptional inhibition of BACE1, resulting in blockade of A? generation in neurons overexpressing human A?-precursor protein. Consistent with reduced A? 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-A? prevention therapy for early-stage AD.

SUBMITTER: Lazic D 

PROVIDER: S-EPMC6363429 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature