Abstract
BackgroundRheumatoid 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.MethodsCIA 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.ResultsBoth 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.ConclusionsNeuroinflammation 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.
Highlights
Rheumatoid arthritis (RA) is characterized by synovial inflammation, cartilage damage, and systemic inflammation
Systemic inflammation and neuroinflammation in collagen-induced arthritis (CIA) rats The symptoms of CIA rats were characterized by the enlargement of paw volume and the change of body weight (Supplementary Figure 1)
6, and Tumor necrosis factor-alpha (TNF-α) were significantly higher in CIA rats than in controls (Fig. 1a)
Summary
Rheumatoid arthritis (RA) is characterized by synovial inflammation, cartilage damage, and systemic inflammation. Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disorder that is characterized by synovial inflammation, cartilage damage, and systemic inflammation. Proinflammatory cytokines, such as interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), are the important inflammation-related mediators regulating the disease state of RA [7]. These proinflammatory cytokines can systemically regulate the expression and/or activities of various proteins, including drug-metabolizing enzymes and membrane transporters [21, 49]. It is noted that the association between RA and AD can be confounded by factors such as age, disease diagnosis and status, and medication [31]
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