Receptor for advanced glycation end products up-regulation in cerebral endothelial cells mediates cerebrovascular-related amyloid β accumulation after Porphyromonas gingivalis infection

Cerebrovascular‐related amyloidogenesis is found in over 80% of Alzheimer's disease (AD) cases, and amyloid β (Aβ) generation is increased in the peripheral macrophages during infection of Porphyromonas 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 Aβ influx after P. gingivalis infection to test our hypothesis that Aβ transportation from periphery into the brain, known as “Aβ influx,” is enhanced by P. gingivalis infection. Using cultured hCMEC/D3 cell line, in comparison to uninfected cells, directly infection with P. gingivalis (multiplicity of infection, MOI = 5) significantly increased a time‐dependent RAGE expression resulting in a dramatic increase in Aβ influx in the hCMEC/D3 cells; the P. gingivalis‐up‐regulated RAGE expression was significantly decreased by NF‐κB and Cathepsin B (CatB)‐specific inhibitors, and the P.gingivalis‐increased IκBα degradation was significantly decreased by CatB‐specific inhibitor. Furthermore, the P. gingivalis‐increased Aβ influx was significantly reduced by RAGE‐specific inhibitor. Using 15‐month‐old mice (C57BL/6JJmsSlc, female), in comparison to non‐infection mice, systemic P. gingivalis infection for three consecutive weeks (1 × 108 CFU/mouse, every 3 days, intraperitoneally) significantly increased the RAGE expression in the CD31‐positive endothelial cells and the Aβ loads around the CD31‐positive cells in the mice's brains. The RAGE expression in the CD31‐positive cells was positively correlated with the Aβ loads. These observations demonstrate that the up‐regulated RAGE expression in cerebral endothelial cells mediates the Aβ influx after P. gingivalis infection, and CatB plays a critical role in regulating the NF‐κB/RAGE expression. Cover Image for this issue: https://doi.org/10.1111/jnc.15073
We demonstrated that CatB /NF‐κB‐dependent up‐regulated RAGE expression in cerebral endothelial cells mediates cerebrovascular‐related Aβ influx into brain during P. gingivalis infection. Together with our previous findings of increased Aβ production peripherally by P. gingivalis infection, thus provide a new mechanism for the involvement of periodontitis in the AD pathological process. Cover Image for this issue: https://doi.org/10.1111/jnc.15073