Amyloid β suppresses protein C activation through inhibition of the endothelial protein C receptor (EPCR).

Alzheimer's disease (AD) is known to be associated with microcirculatory injury, capillary blockage, and disruption of the blood-brain barrier. Endothelial dysfunction has also been reported to be associated with AD, but the underlying mechanisms remain to be elucidated. Endothelial protein C receptor (EPCR) is an N-glycosylated type I membrane protein that enhances the activation of protein C. However, the effects of EPCR and protein C in AD are still unknown. In this study, we found that the expression of EPCR was reduced in the brains of β-amyloid precursor protein overexpressing Tg2576 transgenic mice at both the mRNA level and the protein level. However, levels of thrombomodulin (TM) did not undergo any changes. An in vitro study displayed that β-amyloid (Aβ) treatment led to suppression of EPCR along with reduction of protein C activation in mouse primary endothelial cells. Further study revealed that the induction of the c-Jun N-terminal kinase (JNK)/c-Jun pathway plays a causal role in the inhibitory effects of Aβ1-42 on the expression of EPCR. As a transcriptional factor, c-Jun was able to transinactivate the EPCR promoter. Finally, we found that c-Jun silencing or the use of a JNK inhibitor could attenuate the effects of Aβ1-42 in the activation of protein C.