Caspr1 Facilitates sAPP? Production by Regulating ?-Secretase ADAM9 in Brain Endothelial Cells.

ABSTRACT: The expression of contactin-associated protein 1 (Caspr1) in brain microvascular endothelial cells (BMECs), one of the major cellular components of the neurovascular unit (NVU), has been revealed recently. However, the physiological role of Caspr1 in BMECs remains unclear. We previously reported the nonamyloidogenic processing of amyloid protein precursor (APP) pathway in the human BMECs (HBMECs). In this study, we found Caspr1 depletion reduced the levels of soluble amyloid protein precursor ? (sAPP?) in the supernatant of HBMECs, which could be rescued by expression of full-length Caspr1. Our further results showed that ADAM9, the ?-secretase essential for processing of APP to generate sAPP?, was decreased in Caspr1-depleted HBMECs. The reduced sAPP? secretion in Caspr1-depleted HBMECs was recovered by expression of exogenous ADAM9. Then, we identified that Caspr1 specifically regulates the expression of ADAM9, but not ADAM10 and ADAM17, at transcriptional level by nuclear factor-?B (NF-?B) signaling pathway. Caspr1 knockout attenuated the activation of NF-?B and prevented the nuclear translocation of p65 in brain endothelial cells, which was reversed by expression of full-length Caspr1. The reduced sAPP? production and ADAM9 expression upon Caspr1 depletion were effectively recovered by NF-?B agonist. The results of luciferase assays indicated that the NF-?B binding sites are located at -859 bp to -571 bp of ADAM9 promoter. Taken together, our results demonstrated that Caspr1 facilitates sAPP? production by transcriptional regulation of ?-secretase ADAM9 in brain endothelial cells.

SUBMITTER: Tang SY 

PROVIDER: S-EPMC7068801 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature