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胶质纤维酸性蛋白在脑损伤中作用的研究进展

2024-04-30吴永萌马宁李国婧阴怀清

中西医结合心脑血管病杂志 2024年5期
关键词:脑损伤综述结构

吴永萌 马宁 李国婧 阴怀清

摘要 胶质纤维酸性蛋白(GFAP)是成熟星形胶质细胞的标志。GFAP负责星形胶质细胞的细胞结构和机械强度,并支持其邻近神经元的生理功能和维持血脑屏障。通过反应性星形胶质细胞增生,GFAP参与脑损伤、神经退行性疾病的病理生理学过程。综述GFAP的结构、功能、病理生理作用及其在脑损伤中的作用等方面的研究进展,以促进GFAP作为脑损伤生物标志物的潜在临床价值(包括支持性诊断标准、监测疾病进展和提高预后准确性等方面)的研究。

关键词 脑损伤;胶质纤维酸性蛋白;结构;功能;病理生理作用;综述

doi:10.12102/j.issn.1672-1349.2024.05.015

基金项目 山西省自然基金项目(No.20210302124650)

作者单位 1.山西医科大学(太原  030001);2.山西医科大学第一医院(太原  030001)

通讯作者 阴怀清,E-mail:yhq0351@163.com

引用信息 吴永萌,马宁,李国婧,等.胶质纤维酸性蛋白在脑损伤中作用的研究进展[J].中西医结合心脑血管病杂志,2024,22(5):852-856.

星形胶质细胞占中枢神经系统细胞的30%~40%,与神经系统中的其他细胞(包括神经元)建立大量的相互作用[1]。胶质纤维酸性蛋白(glial fibrillary acidic protein,GFAP)是星形胶质细胞的标志性中间纤维[2],在灰质和白质、小脑、脑室下区和颗粒下区的成熟星形胶质细胞及视网膜中的Mueller细胞中表达[1]。脑特异性GFAP位于星形胶质细胞中,在细胞损伤和死亡后释放[3]。GFAP在成人脑损伤中表现出临床预后潜力,包括创伤性脑损伤[4]、中风[5]和神经退行性疾病[6]。新生儿血清GFAP浓度升高与脑室周围白质损伤[7]、体外膜氧合后脑损伤及出生相关缺氧缺血性脑病出院时磁共振异常有关[8],可提高对新生儿脑病神经发育结果的预测[9-11]。现对GFAP的结构、功能、病理生理作用及其在脑损伤中的作用等方面的研究进展进行综述,促进以GFAP作为脑损伤生物标志物的潜在临床价值(包括支持性诊断标准、监测疾病进展和提高预后准确性等方面)的研究。

1 GFAP的结构

GFAP是一种主要存在于星形胶质细胞中,长度为8~12 nm的Ⅲ型中间纤维结构蛋白[12-14],人GFAP基因于1989年克隆[15],该基因定位于染色体17q21,由9个外显子[16]和8个内含子组成,分布在约10 kb的DNA上,产生约3 kb的成熟mRNA[17],以编码432个氨基酸组成的GFAP[1]。主要异构体GFAP-α在中枢神经系统神经胶质细胞和神经元中高度表达,GFAP-β、γ、ε、κ和ζ异构体在中枢神经系统神经元和神经胶质外的组织和细胞类型中表达[18]。GFAP和其他Ⅲ型中间丝蛋白具有相同的结构特性[2],其单体均由氨基末端“头”、中央螺旋“杆”和羧基末端“尾”域组成[17]。头部和尾部结构域无特定结构,高度保守的杆状结构域包含4个主要α-螺旋片段[19]。

2 GFAP的功能

2.1 一般功能

GFAP在中枢神经系统中有重要作用,如细胞通信、血脑屏障形成[20],这些作用的实现主要基于其细胞骨架和支架的功能。

2.1.1 细胞骨架与形态指标

GFAP是星形胶质细胞中细胞和细胞核的支撑系统或“支架”[21],功能之一是为与其他细胞或细胞外基质接触的质膜提供机械支持,且GFAP的表达对大脑正常组织及血脑屏障完整性至关重要。

2.1.2 细胞间连接和通信

GFAP与其他细胞骨架蛋白和桥粒共同作用,参与形成细胞间连接,并锚定细胞-基质连接,促进细胞间通信,以响应细胞信号和内环境变化[22]。

2.1.3 分子相互作用平台

GFAP与功能分子共定位,甚至发生分子结合,还可作为细胞功能蛋白及酶和其底物之间相互作用的平台[22]。

2.1.4 参与细胞分裂

GFAP调控细丝装配,参与星形胶质细胞分裂过程,表现为GFAP头域磷酸化及GFAP在有丝分裂过程中向子细胞分离部位迁移[23]。

2.2 参与突触外神经递质传递

星形胶质细胞是细胞外神经递质、有机阴离子和其他神经活性物质的主要来源之一[22]。GFAP调控星形胶质细胞囊泡运输,通过胞吐作用、囊泡循环和溶酶介导的自噬释放不同递质转運体的运动[23]。因此,GFAP在递质动态平衡中发挥着关键作用,这些转运体有助于清除突触间隙的神经递质以保护神经元免受神经递质过剩的影响[24]。

2.3 导向作用

GFAP的导向作用包括一个弹性细胞骨架网络,该网络与GFAP的重组、运输和膜蛋白回收机制结合,并为星形胶质细胞中功能蛋白的运输和定位提供指南[22]。

3 GFAP的生理病理作用

脑损伤发生时,星形胶质细胞被激活,GFAP上调。作为星形胶质细胞特有的结构蛋白,GFAP为星形胶质细胞提供稳定性,从而影响其形状和运动[25]。因此,GFAP认为是多种神经病理条件下反应性星形胶质细胞的生物标志物。循环中GFAP水平升高可能与神经系统疾病有关,包括创伤性脑损伤[26]、脊髓损伤[1]、缺氧缺血性脑病[27]、急性缺血性脑卒中[28-29]、颅内及蛛网膜下腔出血[30]、多发性硬化[31]、阿尔茨海默病[32-33]、癫痫[34]、Alexander病[35]、抑郁症[36]、神经炎症[37]、糖尿病酮症酸中毒[38]、帕金森病[39]和视神经脊髓炎谱系障碍[40]。GFAP是较多中枢神经系统疾病中脑损伤的潜在生物标志物。

任何中枢神经系统的病理反应中,星形胶质细胞的防御功能均表现为反应性星形胶质细胞增生[41],即由中枢神经系统损伤引发的星形胶质细胞多成分和复杂的重塑,其特征是GFAP表达增加,可促进大量神经保护和促炎因子相关的星形胶质细胞生化和生理的深刻变化,是细胞病理生理学的重要组成部分,GFAP抑制常加重神经病理变化[42]。

尽管反应性星形胶质细胞增生是基因表达和细胞变化的渐进性变化的精细分级连续体,但出于描述和分类的目的,分为3个类别[24]。1)轻度至中度反应性星形胶质细胞增生:少量或不增生的星状胶质细胞;GFAP表达增高,细胞体及突起肥大均只在个别星状胶质细胞区出现,邻近星状胶质细胞的突起无明显混合、交叠或缺失。轻度或中度反应性星形胶质细胞增生通常与轻度非穿透性和非挫伤性损伤、弥漫性先天免疫活化(病毒感染、系统细菌感染)及距离中枢神经系统局灶性病变距离较远有关。上述形态和机能变化是可逆的[43]。2)严重弥漫性反应性星形胶质细胞增生:星形胶质细胞增殖,导致突起显著延长,超出单个星形胶质细胞原有结构域,GFAP表达上调,细胞体和突起明显肥大。相邻星形胶质细胞突起混合和重叠,个别星形胶质细胞结构域模糊和破坏。此变化导致组织结构长期重组,未形成致密屏障。严重的弥漫性反应性星形胶质细胞增生通常发生在严重的局灶性病变、感染或对慢性神经退行性病变有反应的区域周围。3)严重的反应性星形胶质细胞增生伴致密的胶质瘢痕形成:包括与较轻形式相关的变化,如GFAP显著上调及明显的细胞体和突起肥大。胶质瘢痕的形成表现为反应性星形胶质细胞突起明显重叠,单个星形胶质细胞区域消失,星形胶质细胞增殖及致密、狭窄的胶质瘢痕明显形成。病因包括穿透性创伤、严重挫伤、侵袭性感染或脓肿形成、肿瘤、慢性神经变性、系统性炎症损害。

从功能角度分析,反应性星形胶质细胞增生的目的[42]:1)增加对损伤应激神经元的神经保护和营养支持;2)将受损区域与中枢神经系统组织其余部分隔离;3)重建受损血脑屏障;4)在某些情况下,可能促进受损区域周围脑回路重塑。一般认为,一定程度的脑损伤后胶质细胞增生可能有利于脑损伤后的恢复过程,过度的胶质细胞增殖及其相关的神经炎症反应对脑结构和功能的恢复产生负面影响[2]。

反应性星形胶质细胞增生的正面效应:形成屏障,限制病变并防止其扩散[44];减少白细胞浸润,促进血脑屏障修复[45];限制脑卒中和神经创伤中的神经元损失[46];减少损伤后神经元突触的损失[47];限制神经退行性变,减缓神经退行性疾病的发展[48]。负面效应:限制损伤后突触再生[49];限制轴突再生[50];限制脊髓损伤后再生和功能恢复[51];限制神经移植物和神经干/祖细胞的整合[52]。

4 GFAP在脑损伤中的作用

GFAP基因功能获得性突变引起相关蛋白在星形胶质细胞高水平表达,并沉积形成蛋白聚集体,常导致Alexander病,这是一种以星形细胞包涵体为特征的致命神经退行性疾病[53]。GFAP缺失小鼠出现了与脑白质丢失相关的脑积水、异常的髓鞘形成、脑白质血运不良、血脑屏障结构和功能受损、星形细胞结构和功能异常[54]。因此,GFAP的表达对正常白质结构和血脑屏障完整性是必不可少的,其缺失导致迟发性中枢神经系统髓鞘障碍[22]。尽管GFAP缺失小鼠和野生型小鼠海马体超微结构相同,实验发现大鼠海马长时程显著增强[55]。研究小脑时,实验发现长期抑郁在突变体中比野生型要弱得多,在前额叶皮质被针刺伤后,GFAP缺失型小鼠胶质瘢痕形成[56]。这可能是由于反应性星形胶质细胞增生期间发生的波形蛋白上调所致,缺乏GFAP和波形蛋白的星形胶质细胞形成发育不良的胶质瘢痕。由此可见GFAP对诱导反应性星形胶质细胞增生并非是必需的[54]。GFAP缺失的星形胶质细胞在β-淀粉样肽沉积边缘的突起组织不佳,未形成屏障[57],说明GFAP可能是成熟星形胶质细胞抑制大脑中某些类型的高度炎症性病变必需的。GFAP在提供抗张强度方面可能发挥着与角蛋白类似的作用,由于GFAP通过其包裹的末端为血管系统提供结构完整性以应对在物理创伤中类似于摇晃婴儿综合征的剪切力[54],即GFAP缺失小鼠对血管剪切高度敏感。在GFAP基因缺失小鼠中风模型中,实验发现GFAP相关的调节血流功能障碍,表现为短暂的颈动脉阻断导致的局部脑血流量较低,再灌注期间颅内压较高,从而导致脑梗死体积增加,这些结果表明GFAP缺失小鼠对脑缺血的易感性较高[58],提示GFAP在局灶性脑缺血部分再灌注后缺血性脑损伤的过程中发挥着重要作用。GFAP缺失小鼠对脊髓损伤和脑缺血的抵抗力较低,且在神经损伤后出现了神经病行为和特殊的形态分子重排[59]。目前认为GFAP在中枢神经系统中的作用包括抑制成熟脑中神经元的增殖和轴突延伸,形成物理屏障以隔离受损组织,参与小脑运动学习,控制中枢血流,促进血脑屏障,支持髓鞘形成,并提供机械强度。

GFAP在中枢神经系统外的表达较低,其水平升高的主要原因是机械性脑损傷和局部死亡后星形胶质细胞的激活[60]。有研究显示,脑损伤的理想生物标志物是脑组织特异性的,在神经损伤后立即释放入血[61],并准确反映损伤的位置和程度[62]。GFAP在星形胶质细胞死亡后被释放到血液中,因此其是预测新生儿脑损伤的合适生物标志物[63]。GFAP可作为儿童和成人的诊断和预后工具[30,64-65],且与新生儿异常的脑成像对应[62],可预测新生儿缺氧缺血性脑病、早产儿相关性颅内出血、新生儿冠心病脑损伤、体外膜氧合和新生儿先天性心脏病修复期间体外循环的神经发育结果[66]。因此,GFAP水平可反映新生儿颅脑损伤后临床的严重程度和颅内病变程度。2018年美国食品药物管理局授权进行GFAP的血液检测,用于临床诊断脑损伤[1]。

5 小结与展望

GFAP的异常调控和表达在较多脑部疾病发展中发挥关键作用,这些与GFAP相关的疾病通常是可治愈的。今后研究可能侧重于GFAP表达和功能的调控,通过提出关键干预靶点,对控制星形胶质细胞相关脑疾病至关重要。临床证据表明,GFAP是最有研究价值的生物标志物之一,在神经损伤和其他可能的神经疾病方面具有诊断及治疗作用。较好地了解GFAP在疾病中的功能可提高不同治疗方案的可能性,这些治疗方案可能靶向保存星形胶质细胞功能及其对神经元的稳态支持。

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(收稿日期:2023-03-02)

(本文編辑薛妮)

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