胶原诱导关节炎大鼠血脑屏障功能变化及淀粉样β的转位。
Changes of blood-brain-barrier function and transfer of amyloid beta in rats with collagen-induced arthritis.
机构信息
School of Pharmacy, College of Medicine, National Taiwan University, 33 Linsen South Road, Taipei, Taiwan.
Graduate Institute of Clinical Dentistry, Dental School, College of Medicine, National Taiwan University, Taipei, Taiwan.
出版信息
J Neuroinflammation. 2021 Jan 30;18(1):35. doi: 10.1186/s12974-021-02086-2.
BACKGROUND
Rheumatoid arthritis (RA) is characterized by synovial inflammation, cartilage damage, and systemic inflammation. RA is also associated with the occurrence of neuroinflammation and neurodegenerative diseases. In this study, the impacts of RA on the function of the blood-brain barrier (BBB) and the disposition of amyloid beta (Aβ), including BBB transport and peripheral clearance of Aβ, were investigated in rats with collagen-induced arthritis (CIA), an animal model with similarity to clinical and pathological features of human RA.
METHODS
CIA was induced in female Lewis rats. In addition to neuroinflammation, the integrity and function of the BBB were examined. The expression of Aβ-transporting proteins at brain blood vessels was measured. Blood-to-brain influx and plasma clearance of Aβ were determined.
RESULTS
Both microgliosis and astrogliosis were significantly increased in the brain of CIA rats, compared with controls. In terms of BBB function, the BBB permeability of sodium fluorescein, a marker compound for BBB integrity, was significantly increased in CIA rats. Moreover, increased expression of matrix metalloproteinase-3 (MMP-3) and MMP-9 and decreased expression of tight junction proteins, zonula occludens-1 (ZO-1) and occludin, were observed in brain microvessels of CIA rats. In related to BBB transport of Aβ, protein expression of the receptor of advanced glycation end product (RAGE) and P-glycoprotein (P-gp) was significantly increased in brain microvessels of CIA rats. Notably, much higher expression of RAGE was identified at the arterioles of the hippocampus of CIA rats. Following an intravenous injection of human Aβ, significant higher brain influx of Aβ was observed in the hippocampus of CIA rats.
CONCLUSIONS
Neuroinflammation and the changes of BBB function were observed in CIA rats. The increased RAGE expression at cerebral blood vessels and enhanced blood-to-brain influx of Aβ indicate the imbalanced BBB clearance of Aβ in RA.
背景
类风湿性关节炎（RA）的特征是滑膜炎症、软骨损伤和全身炎症。RA 还与神经炎症和神经退行性疾病的发生有关。在这项研究中，我们在胶原诱导性关节炎（CIA）大鼠中研究了 RA 对血脑屏障（BBB）功能和淀粉样β（Aβ）分布的影响，CIA 是一种具有类似人类 RA 临床和病理特征的动物模型。
方法
在雌性 Lewis 大鼠中诱导 CIA。除了神经炎症外，还检查了 BBB 的完整性和功能。测量了脑血管中 Aβ转运蛋白的表达。测定了 Aβ的血脑内流和血浆清除率。
结果
与对照组相比，CIA 大鼠大脑中的小胶质细胞和星形胶质细胞明显增多。就 BBB 功能而言，CIA 大鼠 BBB 完整性标志物荧光素钠的 BBB 通透性明显增加。此外，CIA 大鼠脑微血管中观察到基质金属蛋白酶-3（MMP-3）和 MMP-9 的表达增加，紧密连接蛋白 zonula occludens-1（ZO-1）和闭合蛋白的表达减少。与 Aβ的 BBB 转运有关，CIA 大鼠脑微血管中晚期糖基化终产物受体（RAGE）和 P-糖蛋白（P-gp）的蛋白表达明显增加。值得注意的是，在 CIA 大鼠海马的小动脉中鉴定出 RAGE 的表达更高。静脉注射人 Aβ后，在 CIA 大鼠的海马中观察到 Aβ的脑内流入明显增加。
结论
在 CIA 大鼠中观察到神经炎症和 BBB 功能的变化。脑血管中 RAGE 表达的增加和 Aβ的血脑内流增加表明 RA 中 Aβ的 BBB 清除失衡。
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