Receptor For Advanced Glycation End Products Up-Regulation In Cerebral Endothelial Cells Mediates Cerebrovascular-Related Amyloid Beta Accumulation Afterporphyromonas Gingivalisinfection

Cerebrovascular-related amyloidogenesis is found in over 80% of Alzheimer's disease (AD) cases, and amyloid beta (A beta) generation is increased in the peripheral macrophages during infection ofPorphyromonas gingivalis(P. gingivalis), a causal bacterium for periodontitis. In this study, we focused on receptor for advanced glycation end products (RAGE), the key molecule involves in A beta influx afterP. gingivalisinfection to test our hypothesis that A beta transportation from periphery into the brain, known as "A beta influx," is enhanced byP. gingivalisinfection. Using cultured hCMEC/D3 cell line, in comparison to uninfected cells, directly infection withP. gingivalis(multiplicity of infection, MOI = 5) significantly increased a time-dependent RAGE expression resulting in a dramatic increase in A beta influx in the hCMEC/D3 cells; theP. gingivalis-up-regulated RAGE expression was significantly decreased by NF-kappa B and Cathepsin B (CatB)-specific inhibitors, and theP.gingivalis-increased I kappa B alpha degradation was significantly decreased by CatB-specific inhibitor. Furthermore, theP. gingivalis-increased A beta influx was significantly reduced by RAGE-specific inhibitor. Using 15-month-old mice (C57BL/6JJmsSlc, female), in comparison to non-infection mice, systemicP. gingivalisinfection for three consecutive weeks (1 x 10(8) CFU/mouse, every 3 days, intraperitoneally) significantly increased the RAGE expression in the CD31-positive endothelial cells and the A beta loads around the CD31-positive cells in the mice's brains. The RAGE expression in the CD31-positive cells was positively correlated with the A beta loads. These observations demonstrate that the up-regulated RAGE expression in cerebral endothelial cells mediates the A beta influx afterP. gingivalisinfection, and CatB plays a critical role in regulating the NF-kappa B/RAGE expression.