Sun Fengxian, Jiang Fang, Zhang Na, Li Hua, Tian Weiping, Liu Weiying
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Department of Cardiology, Tianjin Medical University General Hospital, Tianjin, China.
Front Cell Dev Biol. 2020 Sep 8;8:565020. doi: 10.3389/fcell.2020.565020. eCollection 2020.
Alzheimer's disease (AD) is a devastating neurodegenerative disorder that has no effective therapies. Prickle planar cell polarity protein 2 (Prickle2), is an important cytoplasmic regulator of Wnt/PCP signaling. It has been reported that Prickle2 deficiency reduced neurite outgrowth levels in mouse N2a cells and led to autism-like behaviors and hippocampal synaptic dysfunction in mice. However, much less is known about the relationship of Prickle2 to AD pathogenesis. RT-qPCR, Western blot and IHC results showed that the mRNA and protein levels of Prickle2 were reduced in APP/PS1/Tau transgenic (3xTg) mice. Intravenous injection of Prickle2-overexpressing AAV-PHP.eB vectors improved the cognitive deficits in 3xTg mice. We also demonstrated that Prickle2 could repress oxidative stress and neuroinflammation, ameliorate the amyloid β (Aβ) plaque pathology and reduce Tau hyperphosphorylation in APP/PS1 mice. Further investigation of the mechanism of Prickle2 in AD revealed that Prickle2 inhibited Wnt/PCP/JNK pathway in vivo and in vitro. Our results suggest that Prickle2 might be a potential candidate for the diagnosis and treatment of AD.
阿尔茨海默病（AD）是一种毁灭性的神经退行性疾病，目前尚无有效的治疗方法。普列克底物蛋白2（Prickle2）是Wnt/PCP信号通路重要的细胞质调节因子。据报道，Prickle2缺陷会降低小鼠N2a细胞的神经突生长水平，并导致小鼠出现自闭症样行为和海马突触功能障碍。然而，关于Prickle2与AD发病机制之间的关系，人们了解得还很少。逆转录-定量聚合酶链反应（RT-qPCR）、蛋白质免疫印迹法（Western blot）和免疫组化（IHC）结果显示，Prickle2的mRNA和蛋白质水平在APP/PS1/Tau转基因（3xTg）小鼠中降低。静脉注射过表达Prickle2的腺相关病毒PHP.eB载体可改善3xTg小鼠的认知缺陷。我们还证明，Prickle2可以抑制氧化应激和神经炎症，改善淀粉样β蛋白（Aβ）斑块病理，并减少APP/PS1小鼠的Tau蛋白过度磷酸化。对Prickle2在AD中的作用机制的进一步研究表明，Prickle2在体内和体外均抑制Wnt/PCP/JNK信号通路。我们的结果表明，Prickle2可能是AD诊断和治疗的潜在候选物。
