類風溼性關節炎對於神經發炎以及血腦屏障類澱粉蛋白之運輸在大鼠中之影響之探討

Abstract

類風溼性關節炎是一種自體免疫疾病，該疾病最大特徵為關節發炎、軟骨損傷以及系統性發炎，此疾病帶來的系統性發炎可能導致神經發炎等影響，進而和神經退化性疾病的產生有所關連。本篇研究利用膠原蛋白誘發關節炎大鼠動物模型來探討類風濕性關節炎對於神經發炎、血腦屏障的影響，結果指出，除了細胞激素在腦部的上升外，類風溼性關節炎還可能造成微膠細胞和星狀細胞的活化。在血腦屏障方面，可觀察到其通透性上升以及ZO-1、Occludin表現量的下降，除了血腦屏障完整性之外，與-類澱粉蛋白在血腦屏障的運輸相關蛋白的表現也受到該疾病影響，其中RAGE、P-gp在腦部血管的表現量皆顯著上升，同時也觀察到β-類澱粉蛋白較容易從周邊進入海馬迴區域，近一步探討β-類澱粉蛋白在腦部外的清除機制後，更發現血中的可溶性Lrp-1和肝臟的P-gp表現量有所下降。綜上所述，類風溼性關節炎可導致神經發炎以及血腦屏障的功能失調，並可能導致-類澱粉蛋白在中樞運輸及周邊清除上的變化，這些影響可能進一步與神經退化疾病或阿茲海默失智症的發生有關。

Rheumatoid arthritis (RA) is an autoimmune disease, characterized by synovial inflammation, cartilage damage, and systemic inflammation. The systemic inflammation in RA can be associated with the occurrence of neuroinflammation and neurodegenerative diseases, like Alzheimer's disease (AD). In this study, the impacts of RA on neuroinflammation and the blood-brain barrier (BBB) were investigated in collagen induced arthritis (CIA) rats, an animal model exhibiting similar clinical features of human RA. As a result, along with an elevation of brain cytokine levels, the immunofluorescence analysis showed that both microglia activation and astrogliosis were increased in the brain of CIA rats. In terms of BBB function, the BBB permeability of sodium fluorescein, a marker compound for BBB integrity, was significantly increased in CIA rats. Moreover, the expression of tight junction proteins, Zona-occludin 1 and occludin, also decreased in brain capillaries of CIA rats. In addition to the change in BBB integrity, it is noted that the protein expression of the receptor of advanced glycation end product (RAGE) and P-glycoprotein (P-gp), both are important proteins for BBB transport of amyloid beta (Aβ), was significantly increased in brain capillaries of CIA rats. For brain transport of Aβ, hippocampus in CIA rats showed higher levels of Aβ influx from peripheral blood significantly. In addition to the change at the BBB, the levels of plasma sLrp-1 and hepatic P-gp were decreased, of which both are important for peripheral clearance of Aβ. In conclusion, significant neuroinflammation and BBB breakdown were observed in CIA rats, suggesting the link between RA and neurodegenerative disease. The increase of P-gp and RAGE at BBB along with the change in peripheral sLrp-1 and P-gp in CIA rats suggest that deposition of Aβ is altered in RA, which may be implicated in amyloid pathogenesis of neurodegenerative diseases or AD.