State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.
Research Center of Integrated Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital, Southwest Medical University, Luzhou, China.
DNA Cell Biol. 2020 Jun;39(6):1064-1071. doi: 10.1089/dna.2019.5308. Epub 2020 Apr 7.
Neuroinflammation is a critical mechanism responsible for the progression of Alzheimer's disease (AD). Recent studies reveal that Hippo/Yes-associated protein (YAP) signaling pathway is highly associated with a series of inflammation-related disorders. Glial cell line-derived neurotrophic factor (GDNF), with its neurotrophic and anti-apoptotic functions for nervous system, has been demonstrated to decrease the expression of proinflammatory mediators. Here we investigated whether Hippo/YAP signaling may affect amyloid-β (Aβ)-induced proinflammatory cytokine production in microglial cells and explored its relationship with the anti-inflammation function of GDNF. The results showed that Aβ induced a decrease in the expression of YAP in microglia cells. YAP agonist XMU-MP-1 or its overexpression in microglial cells caused decreased expression of proinflammatory cytokines, whereas YAP antagonist Verteporfin or knockdown of YAP had the opposite effect. Treatment with GDNF resulted in upregulation of YAP expression and reduced the production of proinflammatory cytokines. Meanwhile YAP knockdown weakened the function of GDNF in microglial cells. In conclusion, Hippo/YAP pathway plays a critical role in effect of GDNF against Aβ-induced inflammatory response in microglia. Targeting GDNF or Hippo/YAP signaling may be promising therapeutic approach for the treatment of AD.
神经炎症是阿尔茨海默病（AD）进展的关键机制。最近的研究表明，Hippo/Yes 相关蛋白（YAP）信号通路与一系列炎症相关疾病高度相关。胶质细胞源性神经营养因子（GDNF）具有神经营养和抗细胞凋亡作用，已被证明可降低促炎介质的表达。在这里，我们研究了 Hippo/YAP 信号是否会影响小胶质细胞中 Aβ诱导的促炎细胞因子的产生，并探讨了其与 GDNF 的抗炎功能之间的关系。结果表明，Aβ诱导小胶质细胞中 YAP 的表达减少。YAP 激动剂 XMU-MP-1 或其在小胶质细胞中的过表达导致促炎细胞因子的表达减少，而 YAP 拮抗剂 Verteporfin 或 YAP 的敲低则产生相反的效果。用 GDNF 处理可上调 YAP 的表达并减少促炎细胞因子的产生。同时，YAP 的敲低削弱了 GDNF 在小胶质细胞中的作用。总之，Hippo/YAP 通路在 GDNF 对抗 Aβ诱导的小胶质细胞炎症反应中起关键作用。靶向 GDNF 或 Hippo/YAP 信号可能是治疗 AD 的有前途的治疗方法。
