切换至 "中华医学电子期刊资源库"

中华神经创伤外科电子杂志 ›› 2020, Vol. 06 ›› Issue (05) : 292 -298. doi: 10.3877/cma.j.issn.2095-9141.2020.05.009

所属专题: 文献

基础研究

抗tau蛋白抗体基因疗法对慢性颅脑创伤的治疗作用研究
柴慈婧1, 涂悦2, 张启财2, 侯伊玲1,()   
  1. 1. 300162 天津,武警特色医学中心体检中心
    2. 300162 天津,武警特色医学中心颅脑创伤与神经研究所
  • 收稿日期:2020-06-20 出版日期:2020-10-15
  • 通信作者: 侯伊玲
  • 基金资助:
    国家自然科学基金(81771350)

Study on the therapeutic effect of anti-tau antibody gene therapy on chronic traumatic encephalopathy

Cijing Chai1, Yue Tu2, Qicai Zhang2, Yiling Hou1,()   

  1. 1. Physical Examination Center of Armed Police Medical Center, Tianjin 300162, China
    2. Institute of Traumatic Brain Trauma and Neurology of Armed Police Medical Center, Tianjin 300162, China
  • Received:2020-06-20 Published:2020-10-15
  • Corresponding author: Yiling Hou
  • About author:
    Corresponding author: Hou Yiling, Email:
引用本文:

柴慈婧, 涂悦, 张启财, 侯伊玲. 抗tau蛋白抗体基因疗法对慢性颅脑创伤的治疗作用研究[J]. 中华神经创伤外科电子杂志, 2020, 06(05): 292-298.

Cijing Chai, Yue Tu, Qicai Zhang, Yiling Hou. Study on the therapeutic effect of anti-tau antibody gene therapy on chronic traumatic encephalopathy[J]. Chinese Journal of Neurotraumatic Surgery(Electronic Edition), 2020, 06(05): 292-298.

目的

探究抗tau蛋白(pTau)基因腺病毒相关病毒(AAV)载体中枢神经系统(CNS)直接干预对慢性颅脑创伤(CTE)的治疗效果。

方法

随机选取24只C57小鼠按随机数字表法分为3组,正常对照组(sham组)、CTE 4周组和CTE 12周组,每组8只,采用皮质撞击法建立CTE小鼠动物模型,并在实验开始的第4、12周时取脑组织Western blot检测pTau蛋白相对水平评估该模型;将余56只小鼠按随机数字表法分为7组:sham组、noAAV组、AAVrh.10Null组和编码2B6CisTauIPN007PHF1基因载体组,每组8只,除sham组外,各组小鼠通过皮质撞击法构建CTE模型。第3周时sham组与noAAV组注射等量人工脑脊液,其余各组小鼠分别在海马区注射对应基因编码的表达载体,第4周时所有小鼠安乐死,取脑组织进行免疫荧光和Western blot法评估抗pTau抗体表达,并评估对CTE小鼠的治疗效果。

结果

CTE小鼠模型4和12周组脑组织pTau明显高于sham组,差异均具有统计学意义(P<0.05);AAVrh.10 PHF1与AAVrh.10 IPN治疗组显著降低了小鼠脑组织中pTau的水平,且AAVrh.10 PHF1组优于AAVrh.10 IPN组(P=0.032)。

结论

抗pTau抗体基因的AAVrh.10病毒载体CNS直接治疗CTE有效,为治疗提供了新的方向。

Objective

To investigate the direct intervention of anti-tau protein (pTau) gene adeno-associated virus (AAV) vector in the treatment of chronic traumatic encephalopathy (CTE).

Methods

Twenty-four C57 mice were randomly divided into three groups (n=8), normal control group (sham group), CTE 4 weeks group and CTE 12 weeks group. The CTE mice model was established by cortical impact method. The relative level of pTau protein in brain tissue was detected by Western blot at the 4th and 12th week of the experiment. The remaining 56 mice were randomly divided into 7 groups (n=8): sham group, noAAV group, AAVrh.10Null group and vector group encoding 2B6, CisTau, IPN007 and PHF1 gene vectors. Except for sham group, CTE models were established by cortical impact method. At the 3rd week, the sham group and noAAV group were injected with the same amount of artificial cerebrospinal fluid. The other groups of mice were injected with the corresponding gene encoding expression vector in the hippocampus. At the 4th week, all mice were euthanized. The expression of anti pTau antibody in brain tissue was evaluated by immunofluorescence and Western blot, and the therapeutic effect on CTE mice was also evaluated.

Results

pTau in CTE mice in the 4 and 12 weeks groups was significantly higher than that in sham group, and the difference were statistically significant (P<0.05). Aavrh.10PHF1 and AAVrh.10IPN treatment group significantly reduced the level of pTau in mouse brain tissue, and aAVRh.10PHF1 group was superior to AAVrh.10IPN group (P=0.032).

Conclusion

Direct treatment of AAVrh.10 virus vector CNS with anti-pTau antibody gene is effective and provides a new direction for the treatment of CTE.

图1 脑组织pTau蛋白的相对表达量
图2 抗pTau抗体基因载体AAV治疗后pTau蛋白相对表达量
图3 抗pTau抗体基因治疗后小鼠脑皮层中pTau的水平
表1 3组小鼠水迷宫逃避潜伏期比较(±s,s)
[1]
McKee AC, Stern RA, Nowinski CJ, et al. The spectrum of disease in chronic traumatic encephalopathy[J]. Brain, 2013, 136(Pt 1):43-64.
[2]
Montenigro PH, Baugh CM, Daneshvar DH, et al. Clinical subtypes of chronic traumatic encephalopathy: literature review and proposed research diagnostic criteria for traumatic encephalopathy syndrome[J]. Alzheimers Res Ther, 2014, 6(5): 68.
[3]
Kondo A, Shahpasand K, Mannix R, et al. Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy[J]. Nature, 2015, 523(7561): 431-436.
[4]
Yu YJ, Watts RJ. Developing therapeutic antibodies for neurodegenerative disease[J]. Neurotherapeutics, 2013, 10(3): 459-472.
[5]
Sigurdsson EM. Tau immunotherapies for Alzheimer’s disease and related tauopathies: progress and potential pitfalls[J]. J Alzheimers Dis, 2018, 66(2): 855-856.
[6]
Zhang J, Teng Z, Song Y, et al. Inhibition of monoacylglycerol lipase prevents chronic traumatic encephalopathy-like neuropathology in a mouse model of repetitive mild closed head injury[J]. J Cereb Blood Flow Metab, 2015, 35(3): 443-453.
[7]
Rosenberg JB, Kaplitt MG, De BP, et al. AAVrh.10-mediated APOE2 CNS gene therapy for APOE4-associated Alzheimer’s disease[J]. Hum Gene Ther Clin Dev, 2018, 29(1): 24-47.
[8]
De BP, Heguy A, Hackett NR, et al. High levels of persistent expression of alphal-antitrypsin mediated by the nonhuman primate serotype rh.10 adeno-associated virus despite preexisting immunity to common human adeno-associated viruses[J]. Mol Ther, 2015, 13(1): 67-76.
[9]
Liu W, Zhao L, Blackman B, et al. Vectored intracerebral immunization with the anti-tau monoclonal antibody PHF1 markedly reduces Tau pathology in mutant Tau transgenic mice[J]. J Neurosci, 2016, 36(49): 12425-12435.
[10]
Lee SH, Le Pichon CE, Adolfsson O, et al. Antibody-mediated targeting of tau in vivo does not require effector function and microglial engagement[J]. Cell Rep, 2016, 16(6): 1690-1700.
[11]
Bright J, Hussain S, Dang V, et al. Human secreted tau increases amyloid-beta production[J]. Neurobiol Aging, 2015, 36(2): 693-709.
[12]
Nakamura K, Greenwood A, Binder L, et al. Proline isomer-specific antibodies reveal the early pathogenic tau conformation in Alzheimer’s disease[J]. Cell, 2012, 149(1): 232-244.
[13]
De BP, Chen A, Rosenberg JB, et al. In vivo potency assay for AAV-based gene therapy vectors[J]. Molecular Therapy, 2016, 24(1): S186.
[14]
Stein TD, Alvarez VE, Mckee AC. Chronic traumatic encephalopathy: a spectrum of neuropathological changes following repetitive brain trauma in athletes and military personnel[J]. Alzheimers Res Ther, 2014, 6(1): 4.
[15]
Abbott NJ. Blood-brain barrier structure and function and the challenges for CNS drug delivery[J]. J Inherit Metab Dis, 2013, 36(3): 437-449.
[16]
Lee B, Leavitt MK, Bernick C, et al. A systematic review of positron emission tomography of tau, amyloid beta, and neuroinflammation in chronic traumatic encephalopathy: the evidence to date[J]. J Neurotrauma, 2018, 35(17): 2015-2024.
[17]
Bolós M, Llorens-Martín M, Jurado-Arjona J, et al. Direct evidence of internalization of tau by microglia in vitro and in vivo[J]. J Alzheimers Dis, 2016, 50(1): 77-87.
[18]
Shim SS, Stutzmann GE. Inhibition of glycogen synthase kinase-3: an emerging target in the treatment of traumatic brain injury[J]. J Neurotrauma, 2016, 33(23): 2065-2076.
[19]
Shi H, Hua X, Kong D, et al. Role of toll-like receptor mediated signaling in traumatic brain injury[J]. Neuropharmacology, 2019, 145(Pt B): 259-267.
[20]
Makani V, Zhang B, Han H, et al. Evaluation of the brain-penetrant microtubule-stabilizing agent, dictyostatin, in the PS19 tau transgenic mouse model of tauopathy[J]. Acta Neuropathol Commun, 2016, 4(1): 106.
[21]
Jennings JS, Gerber AM, Vallano ML. Pharmacological strategies for neuroprotection in traumatic brain injury[J]. Mini Rev Med Chem, 2008, 8(7): 689-701.
[22]
Uteshev VV, Tenovuo O, Gaidhani N. The cholinergic potential, the vagus nerve and challenges in treatment of traumatic brain injury[J]. Curr Pharm Des, 2016, 22(14): 2083-2092.
[23]
Stoller KP. All the right moves: the need for the timely use of hyperbaric oxygen therapy for treating TBI/CTE/PTSD[J]. Med Gas Res, 2015, 5: 7.
[24]
Albayram O, Kondo A, Mannix R, et al. Cis P-tau is induced in clinical and preclinical brain injury and contributes to post-injury sequelae[J]. Nat Commun, 2017, 8(1): 1000.
[25]
Spillantini MG, Schmidt ML, Lee VM, et al. Alpha-synuclein in Lewy bodies[J]. Nature, 1997, 388(6645): 839-840.
[26]
Johnson VE, Stewart W, Arena JD, et al. Traumatic brain injury as a trigger of neurodegeneration[J]. Adv Neurobiol, 2017, 15: 383-400.
[27]
Meraz-Ríos MA, Toral-Rios D, Franco-Bocanegra D, et al. Inflammatory process in Alzheimer’s disease[J]. Front Integr Neurosci, 2013, 7: 59.
[28]
Hovakimyan A, Antonyan T, Shabestari SK, et al. A MultiTEP platform-based epitope vaccine targeting the phosphatase activating domain (PAD) of tau: therapeutic efficacy in PS19 mice[J]. Sci Rep, 2019, 9(1): 15455.
[29]
Boluda S, Iba M, Zhang B, et al. Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains[J]. Acta Neuropathol, 2015, 129(2): 221-237.
[30]
Sankaranarayanan S, Barten DM, Vana L, et al. Passive immunization with phospho-tau antibodies reduces tau pathology and functional deficits in two distinct mouse tauopathy models[J]. PLoS One, 2015, 10(5): e0125614.
[1] 丁妍, 文华轩, 陈芷萱, 曾晴, 张梦雨, 廖伊梅, 罗丹丹, 秦越, 梁美玲, 邹于, 李胜利. 胎儿小脑皮质发育不良的产前超声诊断[J]. 中华医学超声杂志(电子版), 2023, 20(03): 255-264.
[2] 丁妍, 文华轩, 张梦雨, 陈思齐, 温昕, 彭桂艳, 曾晴, 罗丹丹, 廖伊梅, 秦越, 梁美玲, 李胜利. 胎儿小脑表面叶裂的产前超声研究[J]. 中华医学超声杂志(电子版), 2023, 20(01): 14-22.
[3] 廖雄宇, 邱坤银, 覃丽君, 何展文. 儿童髓鞘少突胶质细胞糖蛋白抗体相关炎性脱髓鞘疾病临床分析[J]. 中华妇幼临床医学杂志(电子版), 2021, 17(03): 311-320.
[4] 李玉静, 陈七一, 谢汝明, 陈步东. 获得性免疫缺陷综合征相关原发性中枢神经系统淋巴瘤的预后研究[J]. 中华实验和临床感染病杂志(电子版), 2023, 17(03): 200-208.
[5] 李倩, 邓莉平, 陈果, 张忠威, 莫平征, 胡文佳, 陈良君, 张捷, 张永喜, 杨蓉蓉, 熊勇. 宏基因组二代测序在获得性免疫缺陷综合征合并中枢神经系统感染中的临床应用[J]. 中华实验和临床感染病杂志(电子版), 2023, 17(01): 24-31.
[6] 钱永兵, 杭化莲, 张灏旻, 邓羽霄, 陈小松, 夏强. 慢加急性肝衰竭肝移植术后早期并发播散性曲霉病一例[J]. 中华移植杂志(电子版), 2022, 16(05): 306-308.
[7] 韩冰, 王健, 赵帅, 张亦弛, 丁瀚, 顾劲扬. 肝移植术后中枢神经系统曲霉感染一例[J]. 中华移植杂志(电子版), 2021, 15(01): 49-51.
[8] 刘伟华, 赵宇, 刘仲凤, 吴焕童, 张广吉, 陈志国. 神经干细胞生物制剂治疗中枢神经系统恶性肿瘤的研究进展[J]. 中华细胞与干细胞杂志(电子版), 2022, 12(01): 59-62.
[9] 白壮壮, 李东波, 杨倩. 慢性创伤性脑病诊断相关标志物的研究进展[J]. 中华神经创伤外科电子杂志, 2022, 08(05): 302-306.
[10] 蔡霖, 龚秋源, 王伟, 田恒力. 单细胞测序分析技术在小胶质细胞表型异质性研究中的最新进展[J]. 中华神经创伤外科电子杂志, 2021, 07(03): 156-160.
[11] 陈露, 徐蓉, 吴嘉铭, 罗一宁, 廖建成, 李孟辉, 陈克恩, 张茂营. 颅内磷酸盐尿性间叶性肿瘤致骨软化症一例报道并文献复习[J]. 中华脑科疾病与康复杂志(电子版), 2022, 12(01): 54-57.
[12] 刘娟, 朱吉高, 王立兴, 沈力, 傅剑雄. 增强磁共振成像纹理参数对胶质母细胞瘤、原发性中枢神经系统淋巴瘤和单发转移瘤的鉴别诊断价值[J]. 中华消化病与影像杂志(电子版), 2021, 11(02): 61-66.
[13] 牛姗姗, 韩佳悦, 吴文浩, 廖健伟, 罗联美, 张亚琴. 弥散张量成像对于康复期COVID-19患者神经损害的初步研究[J]. 中华介入放射学电子杂志, 2022, 10(04): 422-428.
[14] 刘双, 李道胜, 班媛媛, 滕清良. 原发中枢神经系统的弥漫大B细胞淋巴瘤病理学诊断特征[J]. 中华诊断学电子杂志, 2020, 08(04): 265-269.
[15] 宋蕾, 吴寒, 侯双兴, 楼菁菁, 刘兴党. 关于阿尔茨海默病中视网膜和视神经及相关物质的研究进展[J]. 中华脑血管病杂志(电子版), 2022, 16(05): 351-355.
阅读次数
全文


摘要