核苷酸结合寡聚化结构域样受体3炎症小体:阿尔茨海默病发病机制与靶向治疗
Nucleotide-Binding Oligomerization Domain-Like Receptor 3 Inflammatory Corpuscles: Pathogenesis and Targeted Therapy of Alzheimer’s Disease
摘要: 作为固有免疫应答的重要效应器,核苷酸结合寡聚化结构域样受体含pyrin结构域蛋白3 (Nucleotide-binding oligomerization domain-like receptor protein 3, NLRP3)炎症小体通过感知病原相关分子模式和损伤相关分子模式等危险信号分子,在神经炎症调控网络中发挥核心作用。阿尔茨海默病(Alzheimer’s disease, AD)主要病理特征表现为β淀粉样蛋白(Amyloid beta peptide, Aβ)在细胞外沉积所形成的老年斑及过度磷酸化的tau蛋白在神经元聚集形成的神经纤维缠结这两种病理性蛋白异常聚集可诱导细胞内NLRP3炎症小体的构象变化与功能激活。活化的炎症复合体通过caspase-1通路促进炎症因子的分泌,这种级联反应与AD典型病理改变形成正反馈调节环路,加速神经退行性进程。生理状态下存在精细的神经炎症调节网络,但在AD中这些调控往往出现功能障碍,导致神经免疫稳态失衡。针对NLRP3炎症小体的靶向治疗为AD病因学干预提供了新方向,包括人工合成拮抗剂、药物靶向重构和天然成分等。本文综述NLRP3结构及激活,并探索与AD病理蛋白相关性,旨在为AD治疗提供理论依据。
Abstract: As an important effector of innate immune response, nucleotide-binding oligomerization domain-like receptor containing pyrin domain-like receptor protein 3 (NLRP3) inflammatory corpuscles play a core role in the neuroinflammatory regulatory network by sensing dangerous signal molecules such as pathogen-related molecular patterns and injury-related molecular patterns. The main pathological feature of Alzheimer’s disease (AD) is that the abnormal aggregation of senile plaques formed by extracellular deposition of amyloid β-protein (Aβ) and neurofibrillary tangles formed by hyperphosphorylated tau protein in neurons can induce the conformational changes and functional activation of NLRP3 inflammatory corpuscles in cells. The activated inflammatory complex promotes the secretion of inflammatory factors through caspase-1 pathway, and this cascade reaction forms a positive feedback regulation loop with typical pathological changes of AD, which accelerates the process of neurodegeneration. There are fine neuroinflammatory regulatory networks in physiological state, but in AD, these regulatory networks often appear dysfunction, which leads to the imbalance of neuroimmune homeostasis. Targeted therapy for NLRP3 inflammatory corpuscles provides a new direction for AD etiological intervention, including synthetic antagonists, drug targeted reconstruction and natural components. In this paper, the structure and activation of NLRP3 are reviewed, and the correlation between NLRP 3 and pathological proteins of AD is explored, so as to provide theoretical basis for the treatment of AD.
文章引用:李文丽, 周延华. 核苷酸结合寡聚化结构域样受体3炎症小体:阿尔茨海默病发病机制与靶向治疗[J]. 临床医学进展, 2025, 15(7): 1410-1416. https://doi.org/10.12677/acm.2025.1572141

1. 引言

阿尔茨海默病(Alzheimer’s disease, AD)是一种以认知功能进行性减退为特征的神经退行性疾病,其典型病理特征包括β淀粉样蛋白(Amyloid beta peptide, Aβ)在细胞外沉积所形成的老年斑及过度磷酸化的tau蛋白在神经元聚集形成的神经纤维缠结。目前,神经炎症被认为在AD的发生发展中占据核心地位[1]。其中,Aβ及磷酸tau蛋白聚集诱导小胶质细胞过度激活导致核苷酸结合寡聚化结构域样受体3 (Nucleotide-binding oligomerization domain-like receptor protein 3, NLRP3)炎症小体的活化导致慢性炎症反应和细胞焦亡,从而驱动AD的病理进程。本文综述了NLRP3炎症小体激活的机制及其在AD发病机制中的作用,最后讨论了靶向NLRP3炎症小体治疗AD的临床策略进行综述。

2. NLRP3炎症小体的结构、功能

NLRP3炎症小体结构与功能

NLRP3炎症小体是一种细胞质中天然免疫信号复合体,由NLRP3、接头蛋白凋亡相关的斑点样蛋白(Apoptosis-associated speck-like protein, ASC)和天冬氨酸特异性半胱氨酸蛋白酶1前体(Pro-caspase-1)三部分组成,负责识别外源性刺激和内源性危险信号,清除病原体或受损细胞及导致慢性炎症反应[2]

NLRP3属于胞质模式识别受体蛋白,其分子结构包括三个关键功能结构域,包括C末端富含亮氨酸重复序列(Leucine-rich repeat, LRR)结构域、中央三磷酸腺苷酶结构域(Nucleoside triphosphatase domain, NACHT)和N末端含吡啶结构的热蛋白结构域(Pyrin domain, PYD),能识别病原体或细胞损伤信号,组装成NLRP3炎症小体,进而启动炎症反应[3]。其中,LRR负责识别病原体相关分子模式(Pathogen-related molecular patterns, PAMPs)及损伤相关分子模式(Damage-related molecular model, DAMPs),调控NLRP3的激活与抑制。NACHT具有ATP酶活性,利用水解ATP产生的能量,促进NLRP3蛋白的寡聚化。PYD负责与下游衔接蛋白ASC相互作用。ACS是负责连接胞质内受体和caspase-1的衔接蛋白,由N末端PYD结构域和半胱天冬酶募集结构域(Caspase recruitment domain, CARD)两部分组成,为pro-caspase-1活化为caspase-1提供了必要平台[4] [5]

3. NLRP3炎症小体与小胶质细胞活化

小胶质细胞是大脑中最常见的免疫细胞,其源自神经发育过程中单核细胞前体细胞。在机体生命活动中,小胶质细胞肩负着免疫防御和维持体内平衡两项关键职责。此外,它在神经发生进程、神经元回路构建、以及维系神经元健康方面起着重要作用[6]。不同微环境刺激小胶质细胞,可极化不同的功能表型,分别为静息态小胶质细胞(M0型小胶质细胞)、促炎型小胶质细胞(M1型小胶质细胞)及抗炎型小胶质细胞(M2型小胶质细胞)。M0型小胶质细胞处于相对静止的状态,负责检查局部微环境[7]。当大脑受到损伤或炎症刺激时,M0型小胶质细胞极化为M1或M2型极化。M1型小胶质细胞分泌转化生长因子β和白介素10等促炎细胞因子,参与神经炎性反应与损伤,而M2型小胶质细胞分泌抗炎细胞因子和脑源性神经营养因子,抑制神经炎症且修复受损的神经突触连接[8]。小胶质细胞的模式识别受体NLRP3识别外源性或内源性PAMPs和DAMPs,激活下游转录核因子κB (Nuclear factor κB,NF-κB),磷酸化并降解NF-κB抑制蛋白α,NF-κBp65发生核转移,启动靶基因转录,产生大量的NLRP3、IL-1β前体和IL-18前体完成启动过程[9]。Aβ聚集、tau异常磷酸化、线粒体功能障碍、自噬异常作用常见的DAMPs信号参与小胶质细胞NLRP3炎症小体的激活过程[10]。在上述DAMPs作用下,NLRP3结构改变并招募ASC及pro-caspase-1,共同组装形成炎症小体。这一过程可促进caspase-1成熟,成熟的caspase-1负责将pro-IL-1β和pro-IL-18转化为有活性的IL-1β和IL-18,IL-1β和IL-18作为强效的促炎细胞因子,激活下游炎性级联反应导致大量神经元损伤,参与AD进程[11]。此外,caspase-1特异性识别成孔蛋白(Gasdermin D,GSDMD)并对其进行切割,产生为N末端片段,在细胞膜中发生寡聚化并形成GSDMD孔,诱导细胞肿胀和细胞膜裂解,导致小胶质细胞焦亡[5]

4. NLRP3炎症小体激活的负调控

NLRP3炎症小体的正确激活可以帮助抵抗外源性微生物感染和内源性细胞损伤,然而炎症小体的过度激活通常对细胞和身体健康有害[2]。体内细胞通过受体结合和阻断机制、自噬机制或通过干扰相关基因的表达机制,对NLRP3炎症小体激活发挥负调控作用[12]。在基因层面,微小RNA mir-223可抑制NLRP3基因的表达,对NLRP3炎症小体的激活产生负向调控效应[13]。此外,T细胞和干扰素分别通过下调嘌呤能受体P2X7型表达与干扰信号转导和转录激活因子的信号通路抑制NLRP3炎症小体的激活[2]。研究表明,过氧化氢处理可激活NLRP3炎症小体,但减少了体外细胞中信号转导和转录激活因子丝氨酸727的信号转导和磷酸化。钙螯合剂可阻断NLRP3炎症小体激活。但如果信号转导和转录激活因子本身表达减少,即使钙离子被控制,细胞的氧化损伤仍会加重[14]。所以钙离子和信号转导和转录激活因子蛋白分别通过不同的路径影响炎症。此外,多巴胺与一氧化氮均可抑制NLRP3炎症小体的激活。自噬蛋白LC3B可导致活性氧水平降低,抑制NLRP3炎症小体的组装与激活[2]。尽管NLRP3炎症小体的激活存在多种负调控机制,但在AD患者体内,这些调控机制可能出现异常,导致NLRP3炎症小体过度激活,进而推动AD的病理进程。

5. NLRP3炎症小体在AD的病理作用

NLRP3炎症小体在AD病理网络中处于枢纽地位,与Aβ/tau、线粒体功能障碍及氧化应激病理形成多向恶性循环,共同驱动神经退行。

5.1. Aβ对NLRP3炎症小体的激活

细胞外Aβ异常聚集形成的老年斑是AD的主要病理特征。Aβ依赖于淀粉样蛋白前体蛋白通过淀粉样代谢途径所产生的[15]。Aβ可通过多种途径激活NLRP3炎症小体,而激活的NLRP3炎症小体又可促进Aβ的产生和沉积,形成恶性循环,加速AD病理进展。

Aβ作为DAMPs可与小胶质细胞膜上多种受体结合[16],包括:与小胶质细胞表面的Toll样受体4特异性结合,启动下游髓样分化因子88依赖的信号途径,以此激活白细胞介素-1受体相关激酶、肿瘤坏死因子受体相关因子6,最终使核因子κB活化,产生大量的NLRP3、IL-1β前体和IL-18前体[17] [18];与小胶质细胞表面晚期糖基化终末产物受体结合,激活细胞内丝裂原活化蛋白激酶通路调节炎症因子和氧化应激相关基因的表达且激活核因子κB通路促进炎症反应[19]。Aβ聚集会引发局部炎症反应,招募小胶质细胞等免疫细胞。这些细胞在吞噬Aβ的过程中,吞噬体与溶酶体融合形成的吞噬溶酶体稳定性下降,溶酶体相关膜蛋白2A表达降低,导致溶酶体内容物泄漏,其中的组织蛋白酶B释放到细胞质中,激活NLRP3炎症小体。此外,Aβ损伤线粒体功能,导致氧化应激和线粒体DNA释放,进一步加剧NLRP3炎症小体激活[16]。激活的NLRP3炎症小体促使caspase-1活化,活化的caspase-1切割IL-1β前体和IL-18前体,生成具有生物活性的IL-1β和IL-18。IL-1β可通过激活NF-κB信号通路,使β分泌酶基因启动子区域的组蛋白H3发生乙酰化修饰,促进β分泌酶基因转录,从而增加Aβ的生成[20]

Aβ通过多种机制激活NLRP3炎症小体,NLRP3炎症小体反过来促进Aβ蛋白聚集,不断加剧着AD的病理过程。而在NLRP3炎症小体的激活中,除Aβ外,tau蛋白的聚集也扮演着关键角色。

5.2. tau激活NLRP3炎症小体

正常生理状态下,tau蛋白是一种微管相关蛋白,其生理功能是与微管结合并维持微管的稳定性。在AD的病理条件下,tau发生过度磷酸化,导致tau蛋白从微管上解离下来,并聚集形成神经原纤维缠结(Neurofibrillary tangles, NFTs) [21]。NFTs可通过细胞表面受体识别与细胞内毒性信号激活NLRP3炎症小体。异常磷酸化的tau蛋白可以为DAMPs与小胶质细胞表面toll样受体4特异性结合,经NF-kB信号通路诱导NLRP3炎症小体关键组分的转录,触发组装过程[22]。同时,小胶质细胞吞噬NFTs后,溶酶体膜损伤,释放组织蛋白B至胞质,进一步激活NLRP3炎症小体,促进IL-18和IL-1β炎症因子释放到胞外,引起炎症反应[16]。炎症因子又反过来促进tau磷酸化,加重AD病理,如IL-1β等炎症因子能够激活糖原合成酶激酶3β和周期蛋白依赖性激酶5,促进tau蛋白过度磷酸化[22];同时炎症因子抑制负责tau蛋白去磷酸化蛋白磷酸酶2A,进一步加重tau蛋白过度磷酸化[23]

5.3. AD病理特征与NLRP3炎症小体

除了Aβ/tau蛋白与NLRP3炎症小体的相互作用外,线粒体与氧化应激在NLRP3炎症小体的激活中发挥着重要作用。

线粒体损伤释放mtROS/mtDNA激活NLRP3,而NLRP3活化后通过caspase-1破坏线粒体自噬、IL-1β/IL-18加剧氧化损伤,形成“炎症–线粒体损伤”循环,导致神经元能量危机。氧化应激产物直接触发NLRP3组装,而NLRP3激活的炎症因子耗竭抗氧化物质,形成“氧化应激–炎症”放大循环,加速神经元损伤[31]

6. 通过抑制NLRP3炎症小体的激活来控制AD的发作

NLRP3炎症小体在AD发病机制中发挥关键作用,以NLRP3炎症小体为靶点的AD治疗策略新的可能。通过抑制NLRP3炎症小体的激活的药物可分为合成抑制剂、药物重定向及天然成分。

6.1. 合成抑制剂研究

MCC950是一种二芳基磺酰脲类化合物,作为高特异性NLRP3抑制剂之一,通过结合NLRP3 NACHT结构域的Walker B区,抑制ATP水解病并阻断炎症小体组装,在AD小鼠模型中具有促进Aβ清除,抑制tau病理和改善认知功能多重疗效[24]。与之不同,自噬激动剂雷帕霉素能显著减少IL-1β释放,改善AD模型动物认知功能[25]。而核苷逆转录酶抑制剂他武定通过诱导Aβ自噬逆转AD病理[26]。此外,二乙酰对苯二胺其通过改变NF-kB信号通路和降低NLRP3炎症小体增强小胶质细胞吞噬功能[27]。相较于上游的预防性清除,下游阻断更侧重靶向关键分子。阿那白滞素通过拮抗IL-1β受体,在3Tg-AD模型中,减少tau蛋白磷酸化且改善认知功能[25]。此外,β-羟基丁酸酯(β-hydroxybutyrate, BHB)可有效穿过血脑屏障[26]并抑制人单核细胞中NLRP3炎症小体的激活。通过用BHB干预APP/PS1转基因AD小鼠减轻其大脑皮层病理,并改善AD认知功能[28]

6.2. 药物重定向研究

药物重定向是发现已获批或正在研发的药物在治疗其他疾病方面的新用途。由于不同疾病可能存在共同的病理生理机制,同一种药物可以通过影响这些共同机制来干预多种疾病进程。药物重定位能缩短研发周期、降低成本和风险,提高研发成功率。

格列本脲是一种合成的磺酰脲类药物,原型药物可刺激胰岛β细胞释放胰岛素降血糖,又抑制NLRP3炎症小体激活从而减少caspase-1活化和IL-1β分泌。但这种抑制NLRP3需高剂量,可能引发低血糖副作用[24]。为了解决这一副作用,Kuwar团队通过结构域分离技术开发了衍生物JC124,该化合物将抗炎模块与降糖功能解耦,在AD小鼠模型中不仅减少Aβ沉积、改善神经炎症,还显著提升海马神经发生和突触可塑性,且未出现代谢紊乱副作用[29]。与JC124直接作用于NLRP3炎症小体不同,非甾体抗炎药通过阻断APP/PSI小鼠NF-κB介导的NLRP3转录和IL-1β前体生成,抑制NLRP3炎症小体激活,显著改善AD神经炎症[24]

6.3. 天然成分研究

药物重定向为AD治疗带来了新的思路和方向,然而,天然成分因其独特的生物相容性优势,在AD治疗研究中也备受关注。如小白菊内酯不仅通过烷基化半胱氨酸残基来抑制caspase-1的激活,还通过修饰半胱氨酸直接干扰NLRP3的ATP酶活性。最近研究表明,其水溶性类似物VX-765改善AD的病理并改善AD小鼠模型的认知功能。相比于VX-765,初榨椰子油主要通过以下机制改善AD病理:它能够逆转氧化应激和NLRP3基因的异常表达,并具有抗氧化及抗炎作用。初榨椰子油中的多酚成分可减少Aβ的沉积,降低促炎细胞因子水平,恢复血脑屏障功能,并抑制NACHT、LRR和NLRP3炎症小体的活性,从而诱导自噬,延缓AD进程[30]。除了初榨椰子油,萝卜硫素显著下调Aβ1-42肽刺激的THP-1细胞和饱和脂肪酸巨噬细胞中IL-1β合成和NLRP3的表达,是一种有效的抗AD药物。与萝卜硫素类似,玄参处理的AD动物模型抑制IL-1β产生,降低NLRP3蛋白的表达与caspase-1的活性,抑制Aβ的生成和Aβ斑块形成[24]

7. 结语

对AD中小胶质细胞NLRP3炎症小体激活及其相关的机制研究,使人们对NLRP3介导的神经炎症在AD中作用有一个全面的了解,但AD的病理机制不仅局限于神经炎症,还基于它与Aβ聚集、tau异常磷酸化以及线粒体功能障碍等其他相关复杂机制的相互作用。目前NLRP3炎症小体介导的神经炎症是AD治疗的一个希望潜在靶点,但需注意NLRP3炎症小体和其他AD机制之间存在的复杂相互作用。全面认识AD中小胶质细胞NLRP3炎症小体介导的神经炎症机制有助于开发有潜力的AD治疗方法。

基金项目

内蒙古自治区研究生科研创新项目(KC2024048S)。

NOTES

*通讯作者。

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