PART1 destabilized by NOVA2 regulates blood-brain barrier permeability in endothelial cells via STAU1-mediated mRNA degradation

Blood-brain barrier dysfunction is recognized as a precursor of Alzheimer's disease development. Endothelial cells as structural basis of blood-brain barrier were observed tight junction failure in amyloid-beta(1-42)-stimulated environment. In this study, we found NOVA2, PPP2R3A were down-regulated while PART1, p-NF kappa B-p65 were up-regulated in amyloid-beta(1-42)-incubated endothelial cells. Knockdown of either NOVA2 or PPP2R3A and overexpression of PART1 all increased blood-brain barrier permeability. Lower blood-brain barrier permeability was observed in overexpression of NOVA2 and PPP2R3A and knockdown of PART1 and NF kappa B-p65. Same tendencies were found in the tight junction-related proteins expressions. Furthermore, overexpression and knockdown of NOVA2 and PART1 had no effect on cell viability. Mechanistically, NOVA2 overexpression was confirmed to reduce half-life of PART1. PART1 could destabilize PPP2R3A messenger RNA (mRNA) by interacting with STAU1. In addition, p-NF kappa B-p65 functioning as transcription factor reduced the expression of tight junction-related proteins, which was prompted by low protein level of PPP2R3A. Our study highlights the crucial role of NOVA2/PART1/PPP2R3A/p-NF kappa B-p65 pathway in amyloid-kappa(1-42)-incubated endothelial cells to modulating blood-brain barrier permeability through STAU1-mediated messenger RNA degradation, implying a potential mechanism of lncRNA and protein interaction in pathogenesis of Alzheimer's disease.

Automated summary

This study identifies the crucial role of the NOVA2/PART1/PPP2R3A/p-NF κB-p65 pathway in regulating blood-brain barrier permeability in amyloid-β(1-42)-incubated endothelial cells, suggesting a potential mechanism of lncRNA and protein interaction in the pathogenesis of Alzheimer's disease.