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. 2022 Jul 28;47(7):960–966. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2022.210729

环状RNA在阿尔茨海默病发病机制中的作用

Role of circRNA in pathogenesis of Alzheimer’s disease

SHEN Xueyang 1,2, HE Yaling 1, GE Chaoming 1,✉
Editor: 傅 希文
PMCID: PMC10930285  PMID: 36039594

Abstract

Circular RNA (circRNA) is a covalently closed-loop non-coding RNA that exists widely in the transcriptome of eukaryotic cells. It participates in a variety of pathophysiological processes by acting as a microRNA sponge, regulating the level of protein transcription, and interacting with RNA binding proteins. CircRNA is enriched in the cortex, hippocampus, brain white matter, and photoreceptor neurons of aging bodies, and they can be used as a biomarker for neural senescence. The expression levels of circRNA in peripheral blood and synapses in Alzheimer’s disease (AD) patients are increased, which are involved in the occurrence and prognosis of AD. Different circRNAs such as HDAC9, Homer1, Cwc27, Tulp4, and PTK2 can lead to AD pathological changes via increasing amyloid-β deposition, promoting tau protein hyperphosphorylation, aggravating neuroinflammation and mitochondrial dysfunction, which result in the cognitive decline.

Keywords: circular RNA, Alzheimer’s disease, pathogenesis

阿尔茨海默病(Alzheimer’s disease，AD)是一种慢性进行性神经退行性疾病，也是老年人最常见的认知障碍性疾病，影响全球数百万人[1]，其主要临床表现为认知功能(cognition，C)障碍、精神行为(behavior，B)症状和日常生活活动能力(activity，A)下降，即ABC症候群。中、重度AD患者还会出现各种并发症，需要长期进行综合治疗，会给家庭和社会带来沉重的经济负担。研究[2]表明β-淀粉样蛋白(amyloid β-protein，Aβ)沉积、tau蛋白高度磷酸化、基因突变、慢性炎症及代谢紊乱等因素是导致AD发病的重要机制。目前尚无有效的AD治疗方法。因此，如何早期诊断并治疗AD是目前学者们关注的重点。

环状RNA(circular RNA，circRNA)是一种单链共价闭合的环状RNA分子，通常由前体核糖核酸反向剪接而来，下游5'端剪接位点(剪接供体)和上游的3'端剪接位点(剪接受体)相连，从而产生首尾相连的circRNA[3]，由于缺乏游离末端，它不能被核酸外切酶降解，故其比线性RNA更稳定。CircRNA的关键调控机制包括调控基因转录[4]、翻译蛋白质[5-6]、miRNA“海绵”和RNA结合蛋白质相互作用[7-8]。与线性RNA相比，其在人脑和视网膜组织中显著富集[9]，并参与许多疾病的生物学过程，包括肿瘤、AD在内的多种类型神经疾病[10-11]。目前circRNA[如脑变性相关蛋白1反义转录物(cerebellar degeneration-related protein 1 antisense，CDR1as)]被认为是与AD发病相关的关键风险因素[9]，笔者就近年来circRNA在AD中的作用作一综述。

1. AD与circRNA的关系

1.1. CircRNA组蛋白去乙酰化酶9

突触功能障碍和淀粉样前体蛋白(amyloid pre-cursor protein，APP)的异常加工是AD的早期病理特征。突触可塑性的持续破坏最初表现为突触数目的减少，在疾病后期转化为神经元丢失。因此，推测突触减少是AD患者记忆障碍的基础。组蛋白去乙酰化酶9(histone deacetylase 9，HDAC9)定位于人类染色体7p21，是IIa类HDAC家族成员，在脑、骨骼肌、心肌、大动脉内皮细胞、平滑肌细胞中的含量最多[12]，在细胞质内呈高表达[13]，其本身可使组蛋白去乙酰化，从而重塑染色质结构和控制基因表达，在神经系统疾病、多种类型的肿瘤中发挥着重要的作用[14-15]。Lu等[13]证实AD患者和轻度认知障碍患者血清中circRNA HDAC9(circHDAC9)均降低，通过Morris水迷宫实验和高尔基染色发现2月龄APP/PS1小鼠较对照组空间学习/记忆能力明显下降，且miR-138的过表达会抑制突触蛋白-I、突触后致密蛋白-93(postsynaptic density-93，PSD-93)和PSD-95的表达，导致突触损伤。进一步分析得出circHDAC9通过可作为miR-138的“海绵”分子在体外抑制miR-138的表达，减轻AD样表现，其中包括APP异常加工、空间学习/记忆下降、树棘突退化。Zhang等[16]采用real-time PCR技术检测circHDAC9和miR-142-5p水平，发现β-淀粉样多肽1-42(amyloid β1-42，Aβ42)在人神经元细胞中可引发circHDAC9的显著下调和miR-142-5p的显著上调，而Aβ42可诱导神经元细胞损伤，降低细胞活力、促进细胞凋亡、增强炎症反应。接着通过双荧光素酶分析、RNA免疫沉淀法和RNA沉降实验表明circHDAC9可作为miR-142-5p的“海绵”分子，circHDAC9过表达后发挥其“海绵”作用而与miR-142-5p结合，可减轻Aβ42诱导的HN细胞神经毒性。当用黄连素处理后明显看到Aβ42诱导的神经元细胞的细胞活力提高，细胞凋亡和炎症反应降低，黄连素对Aβ42诱导的神经毒性具有保护作用，可作为一种新的治疗药物用于AD的治疗。综上所述，circHDAC9通过不同的信号通路参与AD的病理和生理过程，有望成为一个新的生物标志物，并可为AD提供一个潜在的治疗靶点。

1.2. CircRNA Homer1

Homer1是由诱导即刻早期基因编码、转录和翻译的一种骨架蛋白，参与构成中枢神经系统PSD。Homer1主要分为Homer1a和Homer1b/c两种蛋白。Homer1a蛋白属于即刻早期基因表达，生理条件下几乎不表达，神经元细胞损伤或者被刺激后启动快速表达，而Homer1b/c蛋白则属于构成型蛋白，在体内常规表达[17-18]。CircRNA Homer1(CircHomer1)主要存在于神经元胞体和树突中，在海马中也有大量表达[18]，其在结直肠癌、肝细胞癌[19]、抑郁症[20]、双相情感障碍和精神分裂症[21-22]、神经退行性疾病[18]等中发挥作用。研究[23-25]表明AD患者的circHomer1在大脑的不同区域均被下调。网络共表达和microRNA结合位点预测分析显示circHomer1与所研究的3个性状[AD患者、神经原纤维缠结分期(Braak分期)、临床痴呆评定量表(clinical dementia rating，CDR)]都显著相关。You等[18]发现由线性RNA Homer1转录后的circHOMER1-a是突触可塑性上调最显著的circRNA。Li等[26]研究表明circHomer1的下调可改善甲基苯丙胺诱导的神经毒性。Zimmerman等[22]研究表明：敲除眼眶额叶皮质中的circHomer1会导致与突触功能和精神疾病相关的mRNA亚型的差异表达，而差异表达的mRNA亚型参与了突触传递、突触可塑性的长时程抑制、神经元兴奋和前脉冲抑制。Urdánoz-Casado等[27]报道：线性RNA Homer1和circHomer1(hsa_circ_0073127、hsa_circ_0006916)的表达在AD女性患者的内嗅皮层中均下调，与Homer1 b/c蛋白表达呈正相关，且其表达水平与Aβ负荷呈负相关，表明circHomer1可能在AD早期发展中发挥了重要的作用。Cervera-Carles等[24]研究发现：在AD患者额叶皮质内可检测到circHomer1表达降低，且其表达水平与AD的病理分期(Braak分期)呈负相关(r=-0.178，P<0.05)。以上研究结果表明circHomer1可作为突触病变的生物标志物，也可以作为判断AD严重程度的重要指标，有望在未来作为药物靶点治疗AD。

1.3. CircRNA Cwc27

CircRNA Cwc27(CircCwc27)是一种富含丰富神经元的环状RNA，在大脑中大量表达，尤其在AD患者和小鼠大脑中显著上调，而在心、肝、脾、肺和肾等其他器官上表达较少。其主要定位于皮质和海马的神经元上，且在细胞质中呈高表达，而皮质和海马是AD最易受伤害的大脑区域[28]。富含嘌呤元件结合蛋白A(purine-rich binding protein-alpha，Pur-α)是一种参与大脑发育、突触可塑性和记忆保持的多功能RNA结合蛋白质(RNA binding protein，RBP)，在基因转录调控中起着关键作用[29]。Barbe等[30]发现在Pur-α杂合的小鼠中存在记忆缺陷，对海马CA1~3区的免疫组织化学分析显示神经元总体数量减少，pur-α免疫阳性的神经元和树突的数量也减少。既往研究[31]表明大脑circRNA表达通常取决于发育年龄，但Song等[28]发现从3个月到12个月，野生型小鼠海马的CircCwc27水平略有增加，在Aβ负荷开始前3个月，CircCwc27开始明显增加，并且在APP/PS1小鼠中随年龄增长显著上调。最近有研究[28]证实：CircCwc27直接与Pur-α结合，使Pur-α在细胞质中的保留增多，抑制了Pur-α向AD基因簇启动子的募集，这些启动子包括APP、多巴胺受体D1型(dopamine receptor D1，DRD1)、蛋白磷酸酶1调节因子亚基1B(recombinant protein phosphatase 1，regulatory subunit 1B，PPP1R1B)、神经营养性酪氨酸激酶受体1型(neurotrophic receptor tyrosine kinase 1，NTRK1)和LIM同源盒基因8(LIM homeobox 8，Lhx8)。CircCwc27的下调增强了Pur-α与这些启动子结合的亲和力，导致Pur-α靶点转录的改变，这表明Pur-α是CircCwc27调控基因表达的重要的下游介质。Pur-α过度表达在很大程度上是一种复制CircCwc27敲除的结果，以防止Aβ沉积、认知功能衰退，减少胶质细胞激活和促炎细胞因子产生，从而表现出对AD的神经炎性和神经退行性改变的保护作用。以上研究表明：CircCwc27和Pur-α组成的新调节轴可能在AD中发挥关键作用，CircCwc27有望成为AD的一个新的治疗靶点，并可作为早期诊断及判断患者预后的一种有效手段。

1.4. CircRNA Tulp4

神经元变性和突触改变被认为是构成AD认知功能障碍的主要神经生物学基础。脊椎动物的Tubby-like蛋白家族(Tubby-like proteins，Tulps)包括Tub和Tulp1~4。Tub和Tulp1~3关系密切，与Tulp4的关系较远。人Tub和Tulp1~3全长有442~561个氨基酸，由12~15个外显子编码，大小为12~15 kb，而Tulp4全长有1 543个氨基酸，由14个外显子编码，大小约为200 kb[32]。人和小鼠的circRNA Tulp4(circTulp4)均由Tulp4基因的第2外显子转录而来。Rybak-Wolf等[33]发现circTulp4富含突触小体，在哺乳动物大脑中高度表达，并在神经元分化过程中上调。同时，circTulp4在人、小鼠心脏中也有丰富的表达，而在大鼠心脏中无表达[34]。Wu等[35]证明在糖尿病模型胰岛β细胞中高表达的circTulp4可通过miR-7222-3p/soat1/cyclin D1信号通路调控β细胞增殖。Chen等[36]发现circTulp4水平降低会导致miR-204-5p和miR-26a-5p靶点的下调，包括体外的MEIS2基因、钙黏着蛋白-2(cadherin 2，CDH2)基因、小眼畸形相关转录因子(melanogenesis associated transcription factor，MITF)基因和磷酸二酯酶4(phosphodiesterase-4B，PDE4B)基因下调，从而影响视网膜的发育和功能。CircTulp4可能参与AD的发展。如Ma等[37]采用转录组测序(RNA-sequencing，RNA-Seq)技术筛选了APP/PS1小鼠相对于野生型(WT)小鼠表达改变的circRNA序列，确定了circTulp4作为潜在的AD生物标志物。Real-time PCR结果[37]显示：2~12个月大的APP/PS1和WT小鼠的脑组织中存在circTulp4表达；APP/PS1小鼠脑中的circTulp4表达在9和12个月时均低于WT小鼠。通过生物信息学分析、RNA纯化的染色质分离、RNA-蛋白质相互作用的快速预测、染色质免疫沉淀等技术[37]发现：circTulp4主要定位于细胞核内，并与抗U1小核糖核蛋白抗体(U1 small nuclear ribonucleoprotein，U1 snRNP)和RNA聚合酶II相互作用，以调节其亲本基因Tulp4的转录，调节神经元的生长和分化，从而影响神经系统功能和AD的发展。CircTulp4的这种调节功能可能是circTulp4失调与AD发病机制之间的潜在联系。目前有关circTulp4与AD发病机制的研究较少，可进一步研究并明确circTulp4能否在体液中检测到，从而使其成为AD一个新的生物标志物或治疗靶点。

1.5. CircRNA蛋白酪氨酸激酶

蛋白酪氨酸激酶(proteintyrosine kinase，PTK)是一类催化ATP上γ-磷酸转移到蛋白酪氨酸残基上的激酶，能催化多种底物蛋白质酪氨酸残基磷酸化，在细胞生长、增殖、分化中具有重要作用。AD患者脑组织中的PTK及其磷酸化已被发现发生了改变[38]。PTK2基因表达的circRNA形式多样，如hsa_circ_0003221[39-40]、hsa_circ_0008305[41-43]、hsa_circ_0005273[44-46]、hsa_circ_0006421[47]和hsa_circ_0005982[48]等，上述均来源于同一个前体mRNA PTK2，但序列不同。CircRNA PTK(circPTK2)参与许多疾病的发生及发展，如非小细胞肺癌[42]、膀胱癌[40]、肝细胞癌[43]、结直肠癌[44]、卵巢癌[41]、胃癌[47]、多发性骨髓瘤[46]、急性髓细胞白血病[45]、肿瘤相关的恶病质[48]、喉鳞状细胞癌[39]、胶质瘤[49]等。目前体内和体外有关circRNA神经炎症的研究[50]已经证明：神经炎症在AD病理发展中发挥作用，并参与该疾病的发病机制。Aβ的存在和先天免疫分子编码基因的突变使小胶质细胞易受刺激和/或促进其激活，导致炎性细胞因子和趋化因子的不断产生，最终导致神经退行性病变和神经元丢失[51]。近年来，研究[52-54]发现在AD中，miR-137、miR-181c、miR-9等的下调会导致AD的发生。Li等[55]用脂多糖(lipopolysaccharides，LPS)诱导炎症细胞模型，通过real-time RT-PCR测定circPTK2(hsa_circ_0008305)和PTK2的表达，利用生物信息学分析、双荧光素酶分析对高迁移率族蛋白B1(high mobility group protein 1，HMGB1)与miR-181c-5p及circPTK2与miR-181c-5p间的相互作用进行研究，结果发现LPS诱导后触发促炎细胞因子的释放、HMGB1和circPTK2的上调，以及小胶质细胞中miR-181c-5p的下调，且miR-181c-5p是circPTK2的靶点，并与HMGB1结合。CircPTK2通过抑制miR-181c-5p调节LPS诱导的小胶质细胞凋亡。用盲肠结扎穿刺(cecum ligation and puncture，CLP)诱导脓毒症小鼠模型，再通过Morris水迷宫实验和线粒体膜电位(mitochondrial membrane potential，MMP)检测，发现沉默circPTK2可以改善认知功能，恢复MMP水平，抑制细胞凋亡，提高CLP小鼠的存活率。He等[56]报道：在AD小鼠模型中，乙基麦芽酚氧钒可使细胞因子信号转导抑制蛋白1/Janus激酶2/信号转导与转录激活子3(suppressor of cytokine signaling 1/Janus kinase 2/signal transduction and activator of transcription 3，SOCS-1/JAK2/STAT3)信号通路失活，并阻断淀粉样蛋白发生级联反应，从而减弱AD模型中Aβ诱导的胰岛素抵抗。同样，Wang等[57]通过构建糖氧剥夺(oxygen glucose deprivation，OGD)离体脑缺血模型，采用生物信息学分析、real-time RT-PCR、荧光素酶分析等技术研究miR-29b和circPTK2间的关系，以及circPKT2在小胶质细胞介导的神经元凋亡中的作用，结果发现circPTK2和miR-29b共享一个结合位点；荧光素酶活性测定显示circPTK2可直接与miR-29b结合，circPTK2通过miR-29b-SOCS-1-JAK2/STAT3-IL-1β信号通路调节OGD激活的小胶质细胞诱导的海马神经元凋亡。从上述研究可以推断circPTK2可能通过不同途径参与AD中的小胶质细胞激活，但尚需进一步明确其具体激活途径与AD发生、发展的关系，从而为临床预防或治疗提供新的方向及思路。

1.6. 其他circRNA对AD的影响

还有许多其他circRNA通过不同途径参与AD的发生和发展，如Lo等[25]通过构建mRNA-circRNA共表达网络发现额下回是circRNA表达最丰富的区域，但海马旁回是circRNA与AD严重程度关系最密切的区域，海马旁回中与AD严重程度呈负相关的模块富集于认知障碍和病理相关通路。Liu等[58]研究发现：在AD患者的外周血中miR-574-5p可能是circRNA hsa_circ_0003391的一种潜在的miR靶点，参与AD的发生和发展。Zhang等[59]通过构建circRNA-ceRNA网络，证实novel_circ_0003012/mmu-miR-298-3p/Smoc2信号轴可能通过影响cGMP-PKG信号通路来调节AD的病理和生理过程。Li等[60]对AD患者脑脊液circRNA表达谱分析发现：circRNA PTK受体基因(circular RNA anexelekto，circAXL)、circRNA桥尾蛋白基因(circular RNA gephyrin，circGPHN)和环状RNA肌醇1,4,5-三磷酸受体3型基因(circular RNA inositol 1,4,5-trisphosphate receptor type 3，circ-ITPR3)是AD风险增高的独立预测因子，可能具有预测AD疾病风险和进展的临床价值。Wu等[61]研究表明环状RNA溶血磷脂酸受体1(circular RNA recombinant lysophosphatidic acid receptor 1，circRNA LPAR1)通过miR-212-3p/锌脂蛋白217(zinc finger protein 217，ZNF217)轴促进Aβ25-35诱导的神经元凋亡、炎症和氧化应激，参与AD的发展。

2. 结 语

AD的发病机制复杂，目前circRNA对AD的作用机制尚不完全清楚，但它已显示出潜在的诊断价值。未来有必要对AD患者进行更大规模的研究，区分疾病的确切阶段、具体变化的脑区和特定的细胞类型，更为详细地描述circRNA变化与AD生理、病理的发生和发展关系，从而探索新的临床前和临床AD生物标志物，为AD的早期诊断及治疗提供新的方法和靶点。

基金资助

甘肃省自然科学基金(20JR10RA719)；兰州市科技局人才创新创业项目(2020-RC-93)。

This work was supported by the Natural Science Foundation of Gansu Province (20JR10RA719) and the Talent Innovation and Entrepreneurship Project of Lanzhou Science and Technology Bureau (2020-RC-93), China.

利益冲突声明

作者声称无任何利益冲突。

作者贡献

沈雪阳 相关文献资料的收集、分析和论文初稿的写作；何亚玲 参与文献资料的分析、整理；葛朝明 项目的构思者及负责人，指导论文写作。

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/202207960.pdf

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