药学学报

Pathway	Target	Strategy	Summary	Ref.
Complement	CR3	Cr3 KO	AβO fails to increase synaptic engulfment in microglia of Cr3 KO mice	[12]
C1q	C1q-blocking antibody ANX-M1;C1qa KO	C1q-blocking antibody or C1qa KO prevents microglial synapse removal and rescues AβO or tau-induced synapse loss in AD mouse models	[12, 23]
C3	C3 KO	Blocking function C3 protects against neurodegeneration in aged plaque-rich APP/PS1 mice, rescues plaque-associated synapse loss in PS2APP mice and ameliorates neuron loss and brain atrophy in tauP301S mice	[12, 24, 25]
C3aR	C3ar KO; C3aR antagonist SB290157	C3ar KO rescues synaptic deficits and neurodegeneration in PS19 mice.Blocking C3aR ameliorates plaque load and microgliosis, restores dendritic morphological and functional deficits, rescues cognitive impairment	[69-71]
CX3CL1/CX3CR1	CX3CR1	Cx3cr1 KO	Microglial Cx3cr1 KO prevents neuron loss in 5xTg-Cx3cr1^-/- mice	[31]
IL-33	IL-33	IL-33	IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice	[56, 57]
TREM2	TREM2	TREM2^R47H, Trem2 KO	A decrease in phagocytosis of postsynaptic elements by microglia expressing TREM2^R47H in the PS19 mice and in human AD brains. TREM2 deficiency attenuates neuroinflammation and neurodegeneration in a mouse model of tauopathy	[40, 41]
Elevated Trem2 gene dosage	Elevated Trem2 gene dosage reprograms microglia responsivity and ameliorates pathology in AD mouse models	[43]
GLT-1	GLT-1	Ceftriaxone	Ceftriaxone upregulates GLT-1 expression, suppresses microglial phagocytosis of synapses, attenuates synaptic and cognitive deficits in rats upon Aβ challenge	[53]
IP3R2-ATP-P2Y1R	P2Y1R, IP3R2	P2Y1R antagonist MRS2179;Itpr2 KO	P2Y1R inhibitors normalizes astroglial and neuronal network dysfunction, augments structural synaptic integrity, and preserves hippocampal long-term potentiation.Itpr2 KO protects from the decline of spatial learning and memory in APP/PS1 mice	[51]
TGF-β1	TGF-β1	TGF-β1	TGF-β1 protects against synapse loss and memory impairment triggered by AβO in AD model	[61]

Pathway	Target	Strategy	Summary	Ref.
Complement	CR3	Cr3 KO	AβO fails to increase synaptic engulfment in microglia of Cr3 KO mice	[12]
C1q	C1q-blocking antibody ANX-M1;C1qa KO	C1q-blocking antibody or C1qa KO prevents microglial synapse removal and rescues AβO or tau-induced synapse loss in AD mouse models	[12, 23]
C3	C3 KO	Blocking function C3 protects against neurodegeneration in aged plaque-rich APP/PS1 mice, rescues plaque-associated synapse loss in PS2APP mice and ameliorates neuron loss and brain atrophy in tauP301S mice	[12, 24, 25]
C3aR	C3ar KO; C3aR antagonist SB290157	C3ar KO rescues synaptic deficits and neurodegeneration in PS19 mice.Blocking C3aR ameliorates plaque load and microgliosis, restores dendritic morphological and functional deficits, rescues cognitive impairment	[69-71]
CX3CL1/CX3CR1	CX3CR1	Cx3cr1 KO	Microglial Cx3cr1 KO prevents neuron loss in 5xTg-Cx3cr1^-/- mice	[31]
IL-33	IL-33	IL-33	IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice	[56, 57]
TREM2	TREM2	TREM2^R47H, Trem2 KO	A decrease in phagocytosis of postsynaptic elements by microglia expressing TREM2^R47H in the PS19 mice and in human AD brains. TREM2 deficiency attenuates neuroinflammation and neurodegeneration in a mouse model of tauopathy	[40, 41]
Elevated Trem2 gene dosage	Elevated Trem2 gene dosage reprograms microglia responsivity and ameliorates pathology in AD mouse models	[43]
GLT-1	GLT-1	Ceftriaxone	Ceftriaxone upregulates GLT-1 expression, suppresses microglial phagocytosis of synapses, attenuates synaptic and cognitive deficits in rats upon Aβ challenge	[53]
IP3R2-ATP-P2Y1R	P2Y1R, IP3R2	P2Y1R antagonist MRS2179;Itpr2 KO	P2Y1R inhibitors normalizes astroglial and neuronal network dysfunction, augments structural synaptic integrity, and preserves hippocampal long-term potentiation.Itpr2 KO protects from the decline of spatial learning and memory in APP/PS1 mice	[51]
TGF-β1	TGF-β1	TGF-β1	TGF-β1 protects against synapse loss and memory impairment triggered by AβO in AD model	[61]

胶质细胞介导的神经突触修剪在阿尔茨海默病中的作用

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李凌杰 ¹^,² , 于晓琳 ^*^,¹ , 刘瑞田 *^,¹

药学学报 | 综述 2021,56(2): 383-390

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药学学报 | 综述 2021, 56(2): 383-390

胶质细胞介导的神经突触修剪在阿尔茨海默病中的作用

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李凌杰¹^,², 于晓琳^*^,¹, 刘瑞田*^,¹

作者信息

1.中国科学院过程工程研究所生化工程国家重点实验室, 北京 100190

2.中国科学院大学化学与化工学院, 北京 100049

通讯作者:

*于晓琳, Tel: 86-10-82545075, E-mail: yuxiaolin@ipe.ac.cn

刘瑞田, Tel: 86-10-82545017, E-mail: rtliu@ipe.ac.cn

Synaptic pruning mediated by glia in Alzheimer's disease

Ling-jie LI¹^,², Xiao-lin YU^*^,¹, Rui-tian LIU*^,¹

Affiliations

1. State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China

2. School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China

出版时间: 2021-02-12 doi: 10.16438/j.0513-4870.2020-1640

文章导航

摘要

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阿尔茨海默病(Alzheimer's disease, AD)是一种以记忆丧失、认知障碍为主要特征的神经退行性疾病, 迄今尚无有效的治疗策略。神经突触是大脑神经元之间联系的部位, 是产生记忆及其他神经活动的关键组成部分, 神经突触的丢失是AD的重要病理特征。胶质细胞是大脑中除神经元以外的一类至关重要的细胞, 其中最主要的两类胶质细胞为小胶质细胞和星形胶质细胞。胶质细胞在维持大脑健康神经环路和调节神经突触可塑性方面扮演着重要角色。在正常生理状态下, 胶质细胞通过修剪多余的神经突触构建和维持成熟的中枢神经网络。然而, 在AD的发生和发展过程中, 胶质细胞对神经突触过度地修剪和清除, 导致突触大量丢失, 引发神经元功能紊乱或死亡, 从而造成认知能力损伤。基于此, 本文拟对目前AD中小胶质细胞和星形胶质细胞参与突触修剪的可能机制进行综述, 以期为AD治疗药物的研发提供崭新的思路。

关键词

阿尔茨海默病 / 认知障碍 / 小胶质细胞 / 星形胶质细胞 / 突触修剪

Abstract

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Alzheimer's disease(AD) is a neurodegenerative disease characterized by memory loss and cognitive impairment. To date, however, no disease-modifying strategies to prevent or cure AD exist. Synapses are involved in the connection of neurons and present as the key component for the memory and other neural activities. Synapse loss is a critical hallmark of AD pathology. In brain, glia cells, including microglia and astrocytes, are a group of highly specific cell types other than neurons. Microglia and astrocytes play a key role in maintaining the healthy neural circuit and regulating synaptic plasticity. Under development and physiological conditions, glial cells contribute to construct and maintain mature central neural networks via synaptic pruning. However, during AD pathogenesis, glial cells engulf synapses excessively, which leads to synapse loss, neuronal dysfunction, and cognitive impairment. Here, we review recent advances in our understanding of the underlying mechanisms for glia-mediated synaptic pruning in AD, and provide a novel strategy for the development of AD drugs.

Key words

Alzheimer's disease / cognitive deficit / microglia / astrocyte / synaptic pruning

引用本文

李凌杰, 于晓琳, 刘瑞田. 胶质细胞介导的神经突触修剪在阿尔茨海默病中的作用. 药学学报, 2021 , 56 (2) : 383 -390 . DOI: 10.16438/j.0513-4870.2020-1640

Ling-jie LI, Xiao-lin YU, Rui-tian LIU. Synaptic pruning mediated by glia in Alzheimer's disease[J]. Acta Pharmaceutica Sinica, 2021 , 56 (2) : 383 -390 . DOI: 10.16438/j.0513-4870.2020-1640

正文

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阿尔茨海默病(Alzheimer's disease, AD)是一种常发于老年人的神经退行性疾病, 临床表现为进行性记忆衰退及认知功能障碍。据统计, 目前全球AD患者约5 000万, 预计2050年将达到1.3亿^{[1, 2]}。目前已有数百种治疗AD的药物进行过临床试验, 而被美国食品药品管理局批准的药物只有天门冬氨酸(N-methyl-D-aspartate)受体拮抗剂美金刚(memantine)和乙酰胆碱酯酶(acetylcholinesterase)抑制剂多奈哌齐(donepezil)等5种药物。这些药物只能缓解AD的病状, 治标不治本^[3]。对AD的致病机制研究认为, AD是由β淀粉样蛋白(β-amyloid, Aβ)和微管相关蛋白tau (microtubule associated protein, tau)在脑内异常聚集形成具有毒性作用的寡聚物所致^[4]。因此, 开发以Aβ和tau蛋白为靶点的药物, 如基于Aβ的产生、聚集和清除的药物, 基于tau蛋白聚集和过度磷酸化的药物等, 成为许多国际大制药公司和研究单位的研究热点, 但迄今为止, 巨大的人力物力投入仍未促使特异性治疗药物面世^[5]。所以, 探索并明确AD的致病机制具有十分重要的意义。

目前认为, 大脑中神经突触的丢失和神经元死亡是AD典型的病理特征^[6]。人类大脑由神经元和胶质细胞两类细胞组成, 神经元是构成神经回路的基本单位, 它由胞体和胞体延伸形成的轴突和树突, 以及神经元间相联系的突触构成。数量繁多的神经突触是神经元之间信息传递的关键组件, 是组成神经回路、产生认知记忆的基础^[7]。突触的损伤直接导致神经元功能的紊乱甚至死亡, 突触的过度丢失即可显示认知功能的下降^[8]。在AD中, 神经突触的大量丢失也是患者记忆力下降的最主要原因^[9]。然而, 在正常生理状态下, 大脑中神经突触的数量处于动态平衡中, 对多余的神经突触进行修剪和清除, 维持健康的中枢神经网络是胶质细胞的重要功能。

胶质细胞是大脑中除神经元以外的一类至关重要的细胞, 占大脑细胞数量的一半以上。其中小胶质细胞和星形胶质细胞是两类最重要的胶质细胞。胶质细胞在供给大脑营养支持、调节神经细胞发育、维持神经元功能、参与免疫应答和提供大脑防御等方面发挥着关键作用。研究认为, 胶质细胞与中枢神经网络的构建与维持密切相关^[10]。在发育阶段, 胶质细胞通过吞噬和修剪多余的神经突触, 构建精准的神经回路。在生长成熟阶段, 胶质细胞则能够调节突触可塑性, 维持大脑的学习和记忆功能^[11]。如果胶质细胞正常的吞噬功能受到破坏, 将会导致神经突触形态、数量和功能发生巨大的变化, 引起神经元功能异常及死亡, 造成认知障碍。此外, 胶质细胞还与神经退行性疾病或脑损伤相关的突触丢失和功能紊乱有关。已有报道证实, 在AD中, 神经突触的大量丢失与胶质细胞对突触的过度吞噬关系密切^[12]。然而, 胶质细胞介导的神经突触修剪是个复杂的过程, 详细机制仍然有待阐明。本文将就目前胶质细胞介导突触修剪的潜在机制展开综述。

1 突触修剪概述

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在神经系统发育阶段, 神经元之间会形成过量的突触连接, 随着发育过程的进行, 多余的突触被胶质细胞吞噬清除, 保留下来的功能性突触相互连接形成精确的神经环路, 这种胶质细胞选择性吞噬清除突触的过程叫做突触修剪^{[11, 13]}。在成熟的神经网络中, 突触的连接和活性处于高度的动态平衡中, 该过程也依赖于胶质细胞对低活性突触的持续修剪和清除。胶质细胞调节突触可塑性的作用对于正常的学习和记忆功能是至关重要的。研究表明, 胶质细胞介导的突触修剪在整个生命过程中持续发生, 并且, 突触修剪现象在中枢神经系统的皮层、海马、丘脑、小脑以及外周神经系统的神经肌肉接头等处广泛存在^[14]。突触修剪对突触的成熟、重塑, 神经元的功能以及神经环路的构建和维持具有重要意义。

越来越多的研究发现, 突触修剪异常与多种神经系统疾病, 如AD、自闭症(autism spectrum disorder, ASD)、精神分裂症(schizophrenia, SCZ)和癫痫等有密切联系^[14]。在AD中, 大量Aβ寡聚体结合到突触上, 激活补体级联信号通路, 刺激小胶质细胞以类似正常修剪突触的方式对突触过度吞噬和清除, 引起突触的大量丢失, 导致认知功能障碍^{[15, 16]}。ASD是一种以沟通困难和社交障碍为特征的神经发育系统疾病, 病理特征为脑内存在过量的神经突触连接, 其致病原因可能是胶质细胞不能及时清除多余的突触连接, 而导致的突触修剪功能障碍^[17]。SCZ是一种认知功能损伤和思维障碍的神经系统疾病, 与ASD不同, SCZ患者脑中的兴奋性突触被胶质细胞过度吞噬清除, 导致兴奋性突触和抑制性突触比例失衡, 造成神经回路功能异常^[18]。癫痫是一种神经元异常放电导致的大脑功能障碍的疾病, 该病也与胶质细胞对突触的异常修剪有关^[19]。因此, 深入研究胶质细胞介导的突触修剪机制, 对于明确AD及其他多种神经系统疾病的发病机制具有重要的意义, 并能够为该类疾病的药物研发提供崭新的方向。

2 小胶质细胞介导的突触修剪

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小胶质细胞是中枢神经系统中的固有免疫细胞, 在大脑中发挥免疫监视及吞噬细胞碎片的作用, 其与神经元关系密切, 在AD的发生发展中扮演着重要的角色^[20]。研究表明, 小胶质细胞能够通过多种方式介导神经突触的修剪, 主要方式分述如下:

2.1 补体系统CR3受体

补体系统介导的小胶质细胞对神经突触的修剪是目前研究较为深入的途径。有研究以视网膜发育系统为模型, 发现经典补体组分蛋白1q (complement component 1q, C1q)能够定位并标记需要修剪的突触, 通过小胶质细胞上的补体受体3(complement receptor 3, CR3)介导小胶质细胞对突触的吞噬^[21]。在AD患者大脑中能够检测到补体系统的激活^[22]。AD脑中的Aβ寡聚体结合在突触上, 诱导补体组分C1q的大量产生, 进而引起下游补体蛋白3(complement 3, C3)含量的上升, C3通过与小胶质细胞表面CR3受体结合, 导致小胶质细胞的生理性突触修剪功能被异常激活, 引起小胶质细胞对突触大量吞噬, 最终造成突触丢失和神经元死亡^[12]。应用C1q抗体或敲除C1qa基因的方法功能性阻断C1q, 能够降低Aβ寡聚体诱导的小胶质细胞对突触的过度吞噬, 改善突触丢失情况^{[12, 23]}。此外, 补体成分C3的缺失或敲除Cr3基因也能够改善AD转基因小鼠脑中的突触丢失状况^{[12, 24, 25]}。因此, 阻断补体C1q/C3/CR3途径抑制小胶质细胞对突触的过量吞噬, 或对小胶质细胞进行基因工程改造使其维持正常的吞噬清除功能, 都将是具有前景的AD治疗策略。

2.2 CX3CR1受体

小胶质细胞还能通过趋化因子C-X3-C-基序受体1 (C-X3-C motif chemokine receptor 1, CX3CR1)介导突触的修剪, 这种吞噬信号通路在小胶质细胞对突触的修剪过程中具有重要作用^[26]。趋化因子C-X3-C-基序配体1 (C-X3-C motif chemokine ligand 1, CX3CL1)主要由神经元表达, 其受体CX3CR1则主要在小胶质细胞上表达。在大脑的发育和成熟过程中, CX3CL1/CX3CR1信号对于神经元和小胶质细胞间的交流至关重要, 该信号参与了脑内包括突触修剪等多种生理过程。目前认为, CX3CL1作为可溶性“发现我信号”诱导小胶质细胞对突触进行修剪^[27]。研究发现, 敲除Cx3cl1的幼年和成年小鼠都表现出降低的社会交互能力和提高的重复性行为特征^{[28, 29]}, 这些行为是与突触修剪缺陷密切相关的, 说明小胶质细胞对突触的修剪依赖CX3CL1/CX3CR1信号^[26]。在AD小鼠模型中, 敲除Cx3cr1基因能够降低小胶质细胞对突触的过度吞噬, 减少突触的丢失^{[30, 31]}。然而, AD中CX3CR1介导的小胶质细胞吞噬突触机制仍然有待进一步研究。正确调节CX3CL1/CX3CR1信号轴, 抑制小胶质细胞对突触的过度修剪, 将是一种有潜力的AD治疗策略。

2.3 “不要吃我”信号(CD47)

在免疫系统中, “不要吃我”信号发挥对抗“吃我”信号的作用, 保护细胞不被吞噬。小胶质细胞通过补体系统介导的突触修剪是通过“吃我”信号C1q对需要修剪的突触进行标记的。与之相对, 小胶质细胞还能通过“不要吃我”信号-分化簇47 (cluster of differentiation 47, CD47)保护特定的突触不被修剪^[32]。CD47属于跨膜免疫球蛋白超家族, 作为一种神经元表达的保护性分子, 通过与小胶质细胞表面的信号调节蛋白α(signal regulatory proteinα, SIRPα)结合, 抑制突触吞噬^[33]。敲除Cd47和Sirpα, 表现为小胶质细胞吞噬能力的增加, 导致小胶质细胞对突触的过度修剪, 引起大量的突触丢失^[33]。此外, 有研究设计了一种新型的负载CD47的纳米颗粒, 能够有效避免载药颗粒被外周巨噬细胞吞噬, 高效靶向脑内的小胶质细胞, 对其病理状态进行改造, 从而达到治疗AD的目的^[34]。

2.4 TREM2受体

髓系细胞2表达触发受体(triggering receptor expressed on myeloid cells 2, TREM2)是一种特异性表达于小胶质细胞表面的受体, 是小胶质细胞上的一个关键的“损伤感受器”, 能够通过调节小胶质细胞的吞噬能力, 介导神经突触的重塑^[35]。在大脑发育的早期阶段, TREM2对于小胶质细胞介导的突触修剪是必不可少的, 缺乏TREM2受体导致突触清除受损, 并伴有树突棘密度增加和兴奋性神经传递增强^[36]。研究表明, 暴露在突触上的磷脂酰丝氨酸(phosphatidylserine)可能是TREM2受体的“吃我”信号^{[37, 38]}。TREM2是AD高风险因素之一^[39]。在AD中, TREM2与小胶质细胞介导的突触清除关系密切。病理性的Aβ和tau蛋白聚集在突触上诱发TREM2识别突触上暴露的磷脂酰丝氨酸, 进而导致小胶质细胞对突触的吞噬^[38]。最近的研究发现, 表达TREM2^R47H突变体的AD患者或tau转基因小鼠脑中的胶质细胞对于突触的吞噬能力下降, 且突触丢失、脑萎缩及胶质细胞活化的现象也显著改善, 提示TREM2功能的下调能够降低神经炎症, 改善tau病理引起的神经退行性病变^{[40, 41]}。然而, TREM2对于Aβ病理具有相反的作用, TREM2功能的缺失导致Aβ模型小鼠脑内的小胶质细胞对于Aβ的吞噬和清除能力显著降低^[42], 引起Aβ的积累, 促进Aβ的神经毒性, 而提高TREM2活性对于Aβ病理是有益的^[43]。基于此, 明确TREM2介导小胶质细胞进行突触修剪的作用机制, 并正确理解TREM2在Aβ病理及tau病理中的不同功能表现, 将有助于靶向TREM2的AD治疗策略的研发。

2.5 其他途径

交互反应DNA结合蛋白43 (TAR DNA-binding protein 43, TDP-43)是一种由Tardbp基因编码的DNA-RNA结合蛋白, 研究发现敲除Tardbp能够调节小胶质细胞的吞噬活性, 促进Aβ的吞噬, 但同时也诱导了小胶质细胞对突触的吞噬, 导致突触的丢失^[44]。此外, 补体蛋白4 (complement 4, C4)也能够介导突触的清除。C4敲除表现为小胶质细胞对突触的修剪异常, 能够增加神经系统疾病如SCZ的风险^[45]。还有研究发现小胶质细胞嘌呤能受体P2Y12R(purinergic receptor P2Y12)对于小鼠视网膜系统突触重塑是必须的, P2Y12R缺陷表现为小胶质细胞吞噬突触的效率降低^[46]。

3 星形胶质细胞介导的突触修剪

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星形胶质细胞在中枢神经系统中主要发挥神经元营养支持、能量代谢及维持血脑屏障的作用。与小胶质细胞相同, 星形胶质细胞也能够参与突触修剪过程。研究表明, AD中反应型星形胶质细胞的突触修剪功能下降, 提示星形胶质细胞对于突触的修剪在AD的发生发展中也扮演着重要角色^[47]。目前研究认为, 星形胶质细胞参与的突触修剪通过以下几种方式:

3.1 MEGF10和MERTK受体

星形胶质细胞可以通过两种吞噬受体-多重表皮生长因子样结构域蛋白10 (multiple EGF like domains 10, MEGF10)和Mer酪氨酸激酶(tyrosine-protein kinase Mer, MERTK)介导神经突触的修剪。MEGF10与果蝇和线虫吞噬受体CED-1 (cell death abnormality protein 1)同源, 在星形胶质细胞中特异性表达, MERTK是受体酪氨酸激酶家族成员, 在星形胶质细胞、小胶质细胞和内皮细胞中都有表达。由MEGF10和MERTK作为受体介导的突触修剪过程在小鼠脑中持续存在, 对兴奋性突触及抑制性突触具有同样的修剪能力^[48]。Megf10和Mertk缺陷的小鼠与补体C3缺陷小鼠表现相似, 即脑中存在过量的突触。MEGF10和MERTK介导的星形胶质细胞的修剪能够将活动性弱的突触消除, 从而保证神经回路的精准性和可塑性^[48]。此外, 也有研究表明MEGF10作为一种“吃我信号”C1q的受体介导星形胶质细胞参与凋亡细胞碎片的吞噬, Megf10敲除的小鼠表现出凋亡神经元的增多和星形胶质细胞吞噬功能的下降^[49]。然而, MEGF10和MERTK受体介导的星形细胞对于突触的修剪在AD中的作用机制仍然有待研究。

3.2 IP3R2

星形胶质细胞还可以通过G蛋白偶联受体二型肌醇1, 4, 5-三磷酸受体(type 2 inositol 1, 4, 5-trisphosphate receptor, IP3R2)依赖的方式释放三磷酸腺苷(adenosine-triphosphate, ATP)作用于突触前嘌呤能受体P2Y1R (purinergic receptor P2Y1)从而介导突触的修剪。星形胶质细胞Ca²⁺浓度的变化依赖IP3R2受体介导的钙库释放, 选择性敲除IP3R2受体基因Itpr2干扰星形胶质细胞钙释放, 导致丘脑腹后内侧核(ventral posteromedial nucleus, VPm)突触修剪的减少并伴随脑内ATP水平的降低, 注射ATP或ATP激动剂可以恢复星形胶质细胞介导的突触修剪功能^[50]。ATP可能通过作用于VPm区神经元突触上的P2Y1R受体诱导长时程抑制(long term depression, LTD)对活动性弱的突触进行“惩罚”标记, 从而使得星形胶质细胞对该突触进行修剪^[50]。长期注射P2Y1R拮抗剂能够增强APP/PS1小鼠脑内结构突触的完整性, 纠正胶质细胞和神经元交互网络的功能紊乱, 改善小鼠的空间学习和记忆能力^[51]。因此, 通过干预IP3R2-ATP-P2Y1R通路调节星形胶质细胞介导的突触修剪, 是一种新的治疗靶点。

4 小胶质细胞和星形胶质细胞共同介导的突触修剪

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4.1 GLT-1

星形胶质细胞能够通过谷氨酸转运体1(glutamate transporter 1, GLT-1)与小胶质细胞共同作用参与突触的修剪。GLT-1主要定位于星形胶质细胞表面, 负责脑内95%以上的谷氨酸摄取转运, 从而确保突触间隙谷氨酸含量维持在适当的水平, 防止谷氨酸过度积累导致的神经毒性。研究表明GLT-1功能的异常与AD、帕金森病(Parkinson's disease, PD)和SCZ等多种神经系统疾病相关^[52]。有研究表明, 在小鼠海马CA1区注射Aβ能够诱导星形胶质细胞GLT-1的表达下调以及补体C1q含量的上调, 从而增加小胶质细胞对于突触的吞噬活性, 导致突触的丢失和认知障碍^[53]。通过注射β内酰胺抗生素头孢曲松上调GLT-1的表达, 能够减少C1q的产生, 降低小胶质细胞对突触的吞噬, 改善认知障碍^[53]。此外, 有研究表明, 肝配蛋白A2 (ephrin-A2)敲除的小鼠会加快皮质突触的修剪, 其可能的机制是肝配蛋白A2的敲除导致星形胶质细胞GLT-1表达的降低, 激活经典补体途径, 进而触发小胶质细胞对突触的吞噬^[54]。

4.2 细胞因子

小胶质细胞和星形胶质细胞能够通过分泌细胞因子共同参与突触的修剪。

星形胶质细胞可以通过分泌白细胞介素33 (inter‐leukin 33, IL-33)调节小胶质细胞的吞噬功能。研究表明, 星形胶质细胞来源的IL-33可以通过与其在小胶质细胞表面的白介素1受体样蛋白1 (interleukin 1receptor like 1, IL1RL1)结合促进小胶质细胞对突触的吞噬。IL-33的表达缺陷或其受体Il1rl1的敲除均能够降低小胶质细胞对突触的吞噬, 表现为存在过量的突触和异常的神经回路。相反, 脊髓中注射IL-33能够导致兴奋性突触的清除速率加倍^[55]。因此, IL-33对于神经系统发育过程中正常突触数目的维持和神经回路的完整性是必不可少的^[55]。此外, 有研究表明AD患者脑中IL-33信号通路受损, 向APP/PS1小鼠注射IL-33能够逆转突触可塑性障碍, 改善认知功能^{[56, 57]}。因此, IL-33能够作为一种AD治疗的潜在靶点。

星形胶质细胞也能够通过分泌转化生长因子β(transforming growth factorβ, TGF-β)与小胶质细胞共同作用参与突触的修剪。TGF-β主要包括TGF-β1、TGF-β2和TGF-β3三种亚型。不同亚型的TGF-β在健康大脑和AD进程中扮演着不同角色^[58]。研究表明, 星形胶质细胞来源的可溶性因子TGF-β3诱导神经元C1q含量的上调, 并通过小胶质细胞和补体CR3途径介导突触修剪, TGF-β3和C1q缺失会导致视网膜发育过程中突触修剪障碍并保留过量的突触^[59]。在体外实验中用Aβ寡聚体处理星形胶质细胞, 导致TGF-β2和TGF-β3含量上升, 海马神经元突触后密度蛋白95 (postsynap‐tic density 95)降低^[60]。也有研究表明, 在AD小鼠模型中, 星形胶质细胞来源的TGF-β1能够保护突触, 抑制Aβ寡聚体诱导的海马突触丢失和认知障碍^[61]。基于此, 有研究采用选择性重摄取抑制剂氟西汀来增加星形胶质细胞对于TGF-β1的释放, 从而能够抵抗Aβ寡聚体诱导的神经毒性。因此, 调节TGF-β可作为潜在的AD治疗策略^[62]。

激活的小胶质细胞能够通过分泌细胞因子如IL-1α、肿瘤坏死因子(tumor necrosis factor, TNF)和补体C1q诱导星形胶质细胞向反应型星形胶质细胞(A1)转化, A1型星形胶质细胞的吞噬受体MEGF10和MERTK表达水平降低, 导致星形胶质细胞吞噬髓鞘碎片和突触修剪的能力受损, 使其失去促进神经元生存、生长、发育的能力, 进而引起神经元死亡^[63]。A1型星形胶质细胞广泛存在于多种神经退行性疾病中, 如AD、PD、肌萎缩侧索硬化症(amyotrophic lateral sclerosis)和多发性硬化症(multiple sclerosis)等。在AD患者脑中, A1型星形胶质细胞占星形胶质细胞总数的60%以上。除了分泌毒性因子, 补体蛋白C3的高表达是A1型星形胶质细胞的标记。A1型星形胶质细胞能够上调许多经典补体途径相关基因的表达, 并释放补体成分蛋白, 促进补体介导的小胶质细胞对突触的过度修剪吞噬, 导致神经元的死亡。注射IL-1α、TNF和C1q的中和抗体, 能够阻断星形胶质细胞向A1型转化, 保护神经元功能与活性^[63]。

4.3 载脂蛋白E

在大脑中, 载脂蛋白E (apolipopro‐tein E, APOE)主要由星形胶质细胞分泌, 其作为胆固醇载体主要参与脂质转运和组织修复^[64]。Apoe是AD的高风险基因之一, 存在3种亚型: E2、E3和E4。其中, E4亚型能够显著增加AD的发病风险, 而E2亚型则相反, 能够降低AD的发病风险, 具有神经保护作用^{[65, 66]}。研究显示星形胶质细胞介导突触修剪的能力高度依赖于APOE的亚型, APOE2能够增强星形胶质细胞对突触的吞噬能力, 而APOE4则会降低其吞噬能力^[67]。这种突触修剪途径对于维持正常的突触可塑性是至关重要的^[68]。在AD中, APOE4与病理性Aβ在突触上的定位增多相关, APOE还能够与C1q结合激活经典补体途径^[68]。这些研究表明, APOE在星形胶质细胞和小胶质细胞介导的突触修剪, 以及胶质细胞与神经元的相互交流中都起到重要的作用。

4.4 C3aR受体

C3-C3aR信号轴在胶质细胞介导的突触修剪中也具有重要的作用。研究表明, AD患者脑中的C3与补体蛋白3a受体(complement component3a receptor, C3aR)的表达水平与患者的认知功能呈负相关。在tau转基因小鼠模型中, 星形胶质细胞释放的C3作用于小胶质细胞表面的C3aR受体, 导致小胶质细胞吞噬突触的能力增加, 引起小鼠脑内树突棘密度形态的改变。基因敲除C3ar能够改善小胶质细胞的激活, 降低其对突触的吞噬, 进而改善tau病理^{[69, 70]}。此外, 在AD患者和APP转基因小鼠脑中, Aβ的过量产生和积累, 导致星形胶质细胞NF-κB的激活及C3的大量释放, C3进而与C3aR相互作用, 破坏神经元树突棘形态和神经网络的正常功能, 应用C3aR拮抗剂能够挽救小鼠的认知损伤^[71], 提示阻断C3-C3aR信号轴也是一种有效降低AD中胶质细胞介导的突触过度修剪, 抑制突触丢失的策略。

5 展望

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目前, 大量临床及动物实验研究表明, 胶质细胞在神经退行性疾病中发挥着至关重要的作用。胶质细胞不仅能够吞噬和清除淀粉样蛋白, 而且能够监控和调节神经元的健康状态。在AD中, 胶质细胞对神经突触的生理性修剪发生异常, 导致突触被过度吞噬清除, 突触的大量丢失造成了神经网络的功能紊乱及稳态失衡。然而, AD中胶质细胞介导突触异常修剪的机制尚不明晰。本文总结了目前已有研究报道的AD中胶质细胞与突触修剪相关的各类受体及通路(表 1)。其中, 经典补体级联途径、TREM2、MEGF10和MERTK受体等都在胶质细胞介导的突触吞噬中发挥了重要作用。值得思考的是, 胶质细胞具有“双刃剑”的作用, 例如, 在AD中, 经典补体途径既能够促进小胶质细胞对淀粉样蛋白的清除, 同时也介导突触的丢失^{[12, 25]}。提高胶质细胞TREM2的活性有益于Aβ病理大脑中的Aβ的吞噬清除, 但却导致tau病理大脑中胶质细胞对突触的吞噬能力增加, 造成突触丢失^[41]。所以, 基于AD是一种复杂的、多因素所导致的神经退行性疾病, 在评价胶质细胞对突触修剪的作用时, 需要认真考虑其所处的特定的病理环境。在不同的病理阶段, 采取不同的干预策略调节胶质细胞介导突触修剪的能力, 将有助于推动有效治疗方法的研发。深入探索AD中淀粉样蛋白Aβ或tau寡聚体、神经突触、胶质细胞、神经免疫系统及神经回路之间相互作用的新通路和新靶点, 将为AD及其他多种神经退行性疾病的发病机制及治疗提供新的理论基础, 为攻克该类疾病的药物研发提供突破性思路。

作者贡献: 李凌杰负责撰写论文初稿; 于晓琳和刘瑞田负责修改论文和最终的定稿。

利益冲突: 所有作者均声明不存在利益冲突。

基金

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国家自然科学基金资助项目(81971610)

参考文献

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2021年第56卷第2期

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doi: 10.16438/j.0513-4870.2020-1640

接收时间：2020-10-21
首发时间：2025-12-18
出版时间：2021-02-12

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收稿日期：2020-10-21
修回日期：2020-12-22

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国家自然科学基金资助项目(81971610)

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1.中国科学院过程工程研究所生化工程国家重点实验室, 北京 100190

2.中国科学院大学化学与化工学院, 北京 100049

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*于晓琳, Tel: 86-10-82545075, E-mail: yuxiaolin@ipe.ac.cn

刘瑞田, Tel: 86-10-82545017, E-mail: rtliu@ipe.ac.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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RefWorks
TxT

Pathway	Target	Strategy	Summary	Ref.
Complement	CR3	Cr3 KO	AβO fails to increase synaptic engulfment in microglia of Cr3 KO mice	[12]
C1q	C1q-blocking antibody ANX-M1;C1qa KO	C1q-blocking antibody or C1qa KO prevents microglial synapse removal and rescues AβO or tau-induced synapse loss in AD mouse models	[12, 23]
C3	C3 KO	Blocking function C3 protects against neurodegeneration in aged plaque-rich APP/PS1 mice, rescues plaque-associated synapse loss in PS2APP mice and ameliorates neuron loss and brain atrophy in tauP301S mice	[12, 24, 25]
C3aR	C3ar KO; C3aR antagonist SB290157	C3ar KO rescues synaptic deficits and neurodegeneration in PS19 mice.Blocking C3aR ameliorates plaque load and microgliosis, restores dendritic morphological and functional deficits, rescues cognitive impairment	[69-71]
CX3CL1/CX3CR1	CX3CR1	Cx3cr1 KO	Microglial Cx3cr1 KO prevents neuron loss in 5xTg-Cx3cr1^-/- mice	[31]
IL-33	IL-33	IL-33	IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice	[56, 57]
TREM2	TREM2	TREM2^R47H, Trem2 KO	A decrease in phagocytosis of postsynaptic elements by microglia expressing TREM2^R47H in the PS19 mice and in human AD brains. TREM2 deficiency attenuates neuroinflammation and neurodegeneration in a mouse model of tauopathy	[40, 41]
Elevated Trem2 gene dosage	Elevated Trem2 gene dosage reprograms microglia responsivity and ameliorates pathology in AD mouse models	[43]
GLT-1	GLT-1	Ceftriaxone	Ceftriaxone upregulates GLT-1 expression, suppresses microglial phagocytosis of synapses, attenuates synaptic and cognitive deficits in rats upon Aβ challenge	[53]
IP3R2-ATP-P2Y1R	P2Y1R, IP3R2	P2Y1R antagonist MRS2179;Itpr2 KO	P2Y1R inhibitors normalizes astroglial and neuronal network dysfunction, augments structural synaptic integrity, and preserves hippocampal long-term potentiation.Itpr2 KO protects from the decline of spatial learning and memory in APP/PS1 mice	[51]
TGF-β1	TGF-β1	TGF-β1	TGF-β1 protects against synapse loss and memory impairment triggered by AβO in AD model	[61]

Pathway

Target

Strategy

Summary

Ref.

Complement

CR3

Cr3 KO

AβO fails to increase synaptic engulfment in microglia of Cr3 KO
mice

[12]

C1q

C1q-blocking antibody ANX-M1;C1qa KO

C1q-blocking antibody or C1qa KO prevents microglial synapse
removal and rescues AβO or tau-induced synapse loss in AD mouse models

[12, 23]

C3 KO

Blocking function C3 protects against neurodegeneration in aged plaque-rich APP/PS1 mice, rescues plaque-associated synapse loss
in PS2APP mice and ameliorates neuron loss and brain atrophy in tauP301S mice

[12, 24, 25]

C3aR

C3ar KO; C3aR
antagonist SB290157

C3ar KO rescues synaptic deficits and neurodegeneration in PS19
mice.Blocking C3aR ameliorates plaque load and microgliosis,
restores dendritic morphological and functional deficits, rescues
cognitive impairment

[69-71]

CX3CL1/CX3CR1

CX3CR1

Cx3cr1 KO

Microglial Cx3cr1 KO prevents neuron loss in 5xTg-Cx3cr1^-/- mice

[31]

IL-33

IL-33 administration reverses synaptic plasticity impairment and
memory deficits in APP/PS1 mice

[56, 57]

TREM2

TREM2^R47H, Trem2 KO

A decrease in phagocytosis of postsynaptic elements by microglia
expressing TREM2^R47H in the PS19 mice and in human AD brains. TREM2 deficiency attenuates neuroinflammation and
neurodegeneration in a mouse model of tauopathy

[40, 41]

Elevated Trem2 gene
dosage

Elevated Trem2 gene dosage reprograms microglia responsivity and ameliorates pathology in AD mouse models

[43]

GLT-1

Ceftriaxone

Ceftriaxone upregulates GLT-1 expression, suppresses microglial
phagocytosis of synapses, attenuates synaptic and cognitive deficits
in rats upon Aβ challenge

[53]

IP3R2-ATP-P2Y1R

P2Y1R, IP3R2

P2Y1R antagonist MRS2179;Itpr2 KO

P2Y1R inhibitors normalizes astroglial and neuronal network
dysfunction, augments structural synaptic integrity, and preserves
hippocampal long-term potentiation.Itpr2 KO protects from the
decline of spatial learning and memory in APP/PS1 mice

[51]

TGF-β1

TGF-β1 protects against synapse loss and memory impairment
triggered by AβO in AD model

[61]