Department of Biomedical Sciences, Center for Creative Biomedical Scientists at Chonnam National University, Gwangju 61469, South Korea.
Department of Anatomy, Chonnam National University Medical School, Gwangju 61469, South Korea.
Cell Death Dis. 2017 Oct 12;8(10):e3102. doi: 10.1038/cddis.2017.491.
Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by excessive beta amyloid (Aβ) deposition in brain, leading to blood-brain barrier (BBB) disruption. The mechanisms of BBB disruption in AD are still unclear, despite considerable research. The adipokine adiponectin is known to regulate various metabolic functions and reduce inflammation. Though adiponectin receptors have been reported in the brain, its role in the central nervous system has not been fully characterized. In the present study, we investigate whether adiponectin contributes to the tight junction integrity and cell death of brain endothelial cells under Aβ-induced toxicity conditions. We measured the expression of adiponectin receptors (AdipoR1 and AdipoR2) and the alteration of tight junction proteins in in vivo 5xFAD mouse brain. Moreover, we examined the production of reactive oxygen species (ROS) and the loss of tight junction proteins such as Claudin 5, ZO-1, and inflammatory signaling in in vitro brain endothelial cells (bEnd.3 cells) under Aβ toxicity. Our results showed that Acrp30 (a globular form of adiponectin) reduces the expression of proinflammatory cytokines and the expression of RAGE as Aβ transporters into brain. Moreover, we found that Acrp 30 attenuated the apoptosis and the tight junction disruption through AdipoR1-mediated NF-κB pathway in Aβ-exposed bEnd.3 cells. Thus, we suggest that adiponectin is an attractive therapeutic target for treating BBB breakdown in AD brain.
阿尔茨海默病（AD）是最常见的神经退行性疾病，其特征是大脑中β淀粉样蛋白（Aβ）过度沉积，导致血脑屏障（BBB）破坏。尽管进行了大量研究，但 AD 中 BBB 破坏的机制仍不清楚。脂联素是一种已知的调节各种代谢功能并减少炎症的脂肪因子。尽管已经在大脑中报道了脂联素受体，但它在中枢神经系统中的作用尚未完全阐明。在本研究中，我们研究了脂联素是否有助于在 Aβ诱导的毒性条件下维持脑内皮细胞的紧密连接完整性和细胞死亡。我们测量了体内 5xFAD 小鼠脑中脂联素受体（AdipoR1 和 AdipoR2）的表达以及紧密连接蛋白的变化。此外，我们检查了在 Aβ毒性下体外脑内皮细胞（bEnd.3 细胞）中活性氧（ROS）的产生以及紧密连接蛋白 Claudin 5、ZO-1 和炎症信号的丢失。我们的结果表明，Acrp30（脂联素的球状形式）通过作为 Aβ进入大脑的转运体降低了促炎细胞因子的表达和 RAGE 的表达。此外，我们发现 Acrp30 通过 Aβ暴露的 bEnd.3 细胞中 AdipoR1 介导的 NF-κB 通路减轻了细胞凋亡和紧密连接破坏。因此，我们认为脂联素是治疗 AD 大脑 BBB 破裂的有吸引力的治疗靶点。
