牙龈卟啉单胞菌感染后脑内皮细胞晚期糖基化终产物上调受体介导脑血管相关淀粉样蛋白β积累,Journal of Neurochemistry

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牙龈卟啉单胞菌感染后脑内皮细胞晚期糖基化终产物上调受体介导脑血管相关淀粉样蛋白β积累
Journal of Neurochemistry ( IF 4.2 ) Pub Date : 2020-05-22 , DOI: 10.1111/jnc.15096
Fan Zeng ₁ , Yicong Liu _{2,

3} , Wanyi Huang ₁ , Hong Qing ₄ , Tomoko Kadowaki ₅ , Haruhiko Kashiwazaki ₆ , Junjun Ni _{1,

4} , Zhou Wu _{1,

7}

Affiliation

在超过 80% 的阿尔茨海默病 (AD) 病例中发现与脑血管相关的淀粉样蛋白生成，并且在牙龈卟啉单胞菌( P. gingivalis ) （牙周炎的致病菌）感染期间，外周巨噬细胞中淀粉样蛋白 β (Aβ) 的生成增加。在这项研究中，我们专注于晚期糖基化终末产物 (RAGE) 受体，这是一种参与牙龈卟啉单胞菌感染后 Aβ 流入的关键分子，以检验我们的假设，即 Aβ 从外周转运到大脑，称为“Aβ 流入”，是牙龈卟啉单胞菌感染增强。使用培养的 hCMEC/D3 细胞系，与未感染的细胞相比，直接感染牙龈卟啉单胞菌（感染复数，MOI = 5）显着增加了时间依赖性 RAGE 表达，导致 hCMEC/D3 细胞中 Aβ 流入的显着增加；的P. gingivalis-上调的RAGE表达显著减少NF-κB和组织蛋白酶B（中CatB）特异性抑制剂，和牙龈卟啉菌-增加IκBα降解显著减少特定中CatB抑制剂。此外，RAGE 特异性抑制剂显着降低了牙龈卟啉单胞菌增加的 Aβ 流入。使用 15 个月大的小鼠（C57BL/6JJmsSlc，雌性），与非感染小鼠相比，系统性牙龈卟啉单胞菌感染连续三周（1 × 10 ⁸ CFU/小鼠，每 3 天，腹膜内）显着增加 CD31 阳性内皮细胞中的 RAGE 表达和小鼠大脑中 CD31 阳性细胞周围的 Aβ 负荷。CD31 阳性细胞中的 RAGE 表达与 Aβ 负荷呈正相关。这些观察结果表明，脑内皮细胞中上调的 RAGE 表达介导了牙龈卟啉单胞菌感染后的 Aβ 内流，并且 CatB 在调节 NF-κB/RAGE 表达中起关键作用。

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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.

更新日期：2020-05-22

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