中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (8): 1841-1849.doi: 10.4103/1673-5374.332160

• 原著:退行性病与再生 • 上一篇    下一篇

沉默Crry调节神经炎症细胞因子和补体系统缓解阿尔茨海默病损伤

  

  • 出版日期:2022-08-15 发布日期:2022-01-22
  • 基金资助:
    国家自然科学基金项目(81801054),江苏省自然科学基金项目(BK20180166),无锡市卫计委项目(Q201722), 无锡市卫健委无锡中青年拔尖人才支持计划(HB2020023),中国博士后资助项目

Crry silencing alleviates Alzheimer’s disease injury by regulating neuroinflammatory cytokines and the complement system

Xi-Chen Zhu1, 2, *, Lu Liu1, Wen-Zhuo Dai1, Tao Ma1, 2, *   

  1. 1Department of Neurology, Wuxi No. 2 People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu Province, China; 2Department of Neurology, Wuxi No. 2 People’s Hospital, Affiliated Wuxi Clinical College of Nantong University, Wuxi, Jiangsu Province, China
  • Online:2022-08-15 Published:2022-01-22
  • Contact: Xi-Chen Zhu, PhD, zxc890205@163.com; Tao Ma, PhD, tmadoc@126.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China (No. 81801054), the Natural Science Foundation of Jiangsu Province of China (No. BK20180166), the Wuxi Municipal Health and Family Planning Commission Fund of China (No. Q201722), Wuxi Top Talent Support Program for Young and Middle-aged People of Wuxi Health Committee of China (No. HB2020023), and China Postdoctoral Funding (all to XCZ).

摘要:

最近有研究证实补体因子CR1的表达与磷酸化tau的丰度及阿尔茨海默病易感性有关。然而,CR1在Tau蛋白相关神经退行性疾病中的确切作用尚不清楚。(1)此次实验首先发现Crry基因主要在小胶质细胞中表达。相比于野生型小鼠,P301S小鼠大脑皮质和海马中Crry表达水平显著升高,且Tau蛋白磷酸化水平(AT8、苏氨酸231和丝氨酸262磷酸化位点)和主要的Tau蛋白激酶糖原合成酶激酶3β和细胞周期依赖性激酶5显著升高。(2)紧接着通过慢病毒转染短发夹RNA沉默Crry基因的表达,发现Crry沉默显著降低了Tau蛋白磷酸化水平和糖原合成酶激酶3β和细胞周期依赖性激酶5激酶的活性。Crry沉默减轻了P301S小鼠的神经元凋亡,改善其认知功能缺陷。还发现Crry沉默调控P301S小鼠的神经炎症(白细胞介素1β、肿瘤坏死因子α和白细胞介素6)水平和补体成分(C3和C3b)的水平。(3)结果说明Crry可通过调节tau蛋白病变小鼠模型中的神经炎症和补体系统来减轻tau蛋白磷酸化而改善其认知功能。

https://orcid.org/0000-0001-8468-876X (Xi-Chen Zhu)

关键词: 阿尔茨海默病, 神经变性, tau蛋白病变, 神经炎症, 补体系统, CR1, Crry, 认知功能

Abstract: Complement component (3b/4b) receptor 1 (CR1) expression is positively related to the abundance of phosphorylated microtubule-associated protein tau (tau), and CR1 expression is associated with susceptibility to Alzheimer’s disease. However, the exact role of CR1 in tau protein-associated neurodegenerative diseases is unknown. In this study, we show that the mouse Cr1-related protein Y (Crry) gene, Crry, is localized to microglia. We also found that Crry protein expression in the hippocampus and cortex was significantly elevated in P301S mice (a mouse model widely used for investigating tau pathology) compared with that in wild-type mice. Tau protein phosphorylation (at serine 202, threonine 205, threonine 231, and serine 262) and expression of the major tau kinases glycogen synthase kinase-3 beta and cyclin-dependent-like kinase 5 were greater in P301S mice than in wild-type mice. Crry silencing by lentivirus-transfected short hairpin RNA led to greatly reduced tau phosphorylation and glycogen synthase kinase-3 beta and cyclin-dependent-like kinase 5 activity. Crry silencing reduced neuronal apoptosis and rescued cognitive impairment of P301S mice. Crry silencing also reduced the levels of the neuroinflammatory factors interleukin-1 beta, tumor necrosis factor alpha, and interleukin-6 and the complement components complement 3 and complement component 3b. Our results suggest that Crry silencing in the P301S mouse model reduces tau protein phosphorylation by reducing the levels of neuroinflammation and complement components, thereby improving cognitive function.

Key words: Alzheimer’s disease, cognitive function, complement system, CR1, Crry, neurodegeneration, neuroinflammation, tauopathy