Oligomeric Tau-induced Oxidative Damage and Functional Alterations in Cerebral Endothelial Cells: Role of RhoA/ROCK Signaling Pathway

罗亚 封堵器 法苏迪尔 血脑屏障 紧密连接 细胞生物学 氧化应激 化学 信号转导 势垒函数 Rho相关蛋白激酶 生物 生物化学 中枢神经系统 神经科学
作者
Faruk Hossen,Grace Y. Sun,James C. Lee
出处
期刊:Free Radical Biology and Medicine [Elsevier]
卷期号:221: 261-272 被引量:1
标识
DOI:10.1016/j.freeradbiomed.2024.05.044
摘要

Despite of yet unknown mechanism, microvascular deposition of oligomeric Tau (oTau) has been implicated in alteration of the Blood-Brain Barrier (BBB) function in Alzheimer's disease (AD) brains. In this study, we employed an in vitro BBB model using primary mouse cerebral endothelial cells (CECs) to investigate the mechanism underlying the effects of oTau on BBB function. We found that exposing CECs to oTau induced oxidative stress through NADPH oxidase, increased oxidative damage to proteins, decreased proteasome activity, and expressions of tight junction (TJ) proteins including occludin, zonula occludens-1 (ZO-1) and claudin-5. These effects were suppressed by the pretreatment with Fasudil, a RhoA/ROCK signaling inhibitor. Consistent with the biochemical alterations, we found that exposing the basolateral side of CECs to oTau in the BBB model disrupted the integrity of the BBB, as indicated by an increase in FITC-dextran transport across the model, and a decrease in trans endothelial electrical resistance (TEER). oTau also increased the transmigration of peripheral blood mononuclear cells (PBMCs) in the BBB model. These functional alterations in the BBB induced by oTau were also suppressed by Fasudil. Taken together, our findings suggest that targeting the RhoA/ROCK pathway can be a potential therapeutic strategy to maintain BBB function in AD.
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