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即刻早期基因Arc/Arg3.1的表达及与阿尔茨海默病关系的研究进展

作者 / Author:杨承源 杨惠林 许丽珍 朱奕潼

摘要 / Abstract:

Arc/Arg3.1基因为即刻早期基因(immediate-early genes,IEGs)的一种,是可以直接作为效应因子的细胞结构元件,其在神经元突触可塑性方面起重要的作用。若Arc/Arg3.1蛋白表达受阻则会损坏LTP的维持,继而损坏长期记忆的巩固。阿尔茨海默病(Alzheimer’s disease,AD)患者体内Arc/Arg3.1表达水平异常增高,且Arc/Arg3.1自身表达易被附近的Aβ低聚物和斑块打乱,这种改变可干扰体内神经网络的集成。目前尚不清楚这些改变如何影响AD的神经生理。本文将

关键词 / KeyWords:

Arc/Arg3.1,阿尔茨海默病,突触可塑性,记忆,行为

即刻早期基因Arc/Arg3.1的表达及与阿尔茨海默病关系的研究进展

杨承源1)  杨惠林1)  许丽珍2)  朱奕潼2)△
苏州大学附属第一医院  1)骨科  2)博习诊疗中心,江苏 苏州 215000
△通信作者:朱奕潼(1989-),女,硕士,主治医师。研究方向:脑损伤的功能康复。Email:violetfighting@126.com
摘要】  Arc/Arg3.1基因为即刻早期基因(immediate-early genes,IEGs)的一种,是可以直接作为效应因子的细胞结构元件,其在神经元突触可塑性方面起重要的作用。若Arc/Arg3.1蛋白表达受阻则会损坏LTP的维持,继而损坏长期记忆的巩固。阿尔茨海默病(Alzheimer’s disease,AD)患者体内Arc/Arg3.1表达水平异常增高,且Arc/Arg3.1自身表达易被附近的Aβ低聚物和斑块打乱,这种改变可干扰体内神经网络的集成。目前尚不清楚这些改变如何影响AD的神经生理。本文将对Arc/Arg3.1基因的调控、Arc/Arg3.1蛋白的表达以及在现有AD模型中的研究做一综述。
关键词】  Arc/Arg3.1;阿尔茨海默病;突触可塑性;记忆;行为
中图分类号】  R749.16    【文献标识码】  A    【文章编号】  1673-5110(2018)03-0331-05  DOI:10.12083/SYSJ.2018.03.085
Expression of immediate early gene Arc/Arg3.1 and its relationship with Alzheimer's disease:an update
YANG Chengyuan*,YANG Huilin,XU Lizhen,ZHU Yitong
*Department of Orthopedics,the First Affiliated Hospital of Soochow University,Suzhou 215000,China
Abstract】  Arc/Arg3.1 gene is a member of the immediate early genes family,working as a transcription factor.Arc/Arg3.1plays an important role in synaptic plasticity.Once Arc/Arg3.1 protein expression is hindered,it will damage the LTP and thereby interfere with the long-term memory consolidation.AD patients express anomalously high levels of Arc/Arg3.1 protein.Arc/Arg3.1 expression itself is disrupted in the vicinity of Aβ oligomers and plaques.Such alterations result in the interruption of neuronal network integration in vivo.It is not clear what the impacts of these alterations are on the functional neurophysiology of AD-associated amyloidopathy.This brief review will emphasize the rising role of Arc/Arg3.1 and its involvement in neurophysiological alterations of current AD models.
Key words】  Arc/Arg3.1;Alzheimer's disease;Synaptic plasticity;Memory;Behavior
      阿尔茨海默病(Alzheimer’s disease,AD)是一种进行性神经系统退行性病变,以细胞外淀粉样蛋白沉积及细胞内神经元纤维缠结为病理学特征,并有皮质神经元及轴突的丢失。事实上,早在神经退行性变发生之前,突触已出现明显的功能障碍[1]。突触可塑性指的是神经活动引起的神经元之间信息传递效能增强或减弱的现象[2]。Aβ低聚肽可破坏突触可塑性[3],诱导细胞凋亡[4],抑制啮齿类动物的学习[5]。在海马的神经通路上,高频电刺激可以使海马神经元兴奋性突触后电位(excitation postsynaptic potential,EPSP)增强,称为长时程增强(long-term potentiation,LTP),它是突触可塑性的一种重要形式,被公认为与学习和记忆相关。活性调节细胞骨架相关蛋白(activity-regulated cytoskeletal protein,Arc)/活性调节基因3.1蛋白同系物(activity-regulated gene 3.1 protein homolog,Arg3.1)是一种独特的即早基因(immediate early gene,IEG),与LTP密切相关[6-8]。AD转基因大鼠模型中敲除Arc/Arg3.1基因可以减少Aβ的聚集[9]。同样,临床AD患者反常地表达过高的Arc/Arg3.1,因此,我们推测,Arc/Arg3.1参与AD的病理过程。
      Arc/Arg3.1 cDNA约含3 000个碱基对,最早于1995由LINK和LYFORD所在实验室相继发现,并分别命名为Arc和Arg3.1,此后被用作大脑神经活动的分子标记物。Arc/Arg3.1蛋白在海马神经元的树突上含量丰富,并与树突上的细胞骨架蛋白相关[10]。Arc/Arg3.1基因是单拷贝基因,在脊椎动物中高度保守。有趣的是,Arc/Arg3.1基因缺少序列同源性,在非脊椎动物中尚未发现功能同源染色体[11],提示Arc/Arg3.1在进化晚期出现,对于神经系统可能存在特殊的意义[12]
1  Arc/Arg3.1基因表达的调控
      癫痫发作[13]、神经活动增加[14]、脑源性神经营养因子(brain derived neurotrophic factor,BDNF)[15]、LTP[16]、长时程抑制(long-term depression,LTD)[17]和其他的刺激均可以诱导Arc/Arg3.1基因的表达。Arc/Arg3.1基因表达后能够被迅速运送到活跃的树突区域,并被翻译成对应蛋白,定位在树突突起的底部。当突触活动增强时,Arc/Arg3.1 mRNA和表达的蛋白都显著增加,具有明显的活性依赖性[18]
1.1  Arc/Arg3.1转录的调控  Arc/Arg3.1基因在刺激发生后的5 min内迅速转录,故称其为“即早”基因[14]。这类基因在起始位点下游装有转录装置,故神经元在刺激发生后得以最快的速度发生转录[19]。通常,Arc/Arg3.1以相对低的水平发生转录,AMPA受体激活后其转录水平进一步降低[20]。BDNF TrkB受体[15]、1组代谢型谷氨酸受体[21]、毒蕈碱型乙酰胆碱受体[22]和NMDA受体[23]的激活可极大上调Arc/Arg3.1的转录。细胞外信号调节激酶(extracellular signal-regulated kinase,ERK)是上述信号传导途径下游的一个中心位点,为Arc/Arg3.1转录增强所必需的因子。ERK一旦被激活,即可磷酸化血清反应因子的一个共激活剂,如三元复合物因子中的Elk1。这种复合物结合于启动子区域血清反应元件上,起转录激活的作用[24]。虽然我们并不完全了解Arc/Arg3.1转录过程中受体、信号通路间以及启动子区的相互联系,但Arc/Arg3.1显然为我们了解不同形式的突触活动引发的神经元反应提供了一个特别的切入点。
1.2  Arc/Arg3.1蛋白的产生和降解  和Arc/Arg3.1转录类似,Arc/Arg3.1翻译似乎也受活动水平和特定的信号级联反应的高度调控。在体外培养的神经元中刺激NMDA受体和Gs偶联受体可通过蛋白激酶A作用上调Arc/Arg3.1的翻译水平[25]。体内LTP诱导的Arc/Arg3.1翻译需要ERK信号通路的参与,通过MAP激酶交互激酶磷酸化aIF4E而发挥作用[26]。代谢型谷氨酸受体mGluR-LTD可通过真核细胞延长因子2(eEF2)的磷酸化作用使原有的Arc/Arg3.1 mRNA迅速翻译[17]。翻译后,其稳定性可能受PEST序列和泛素蛋白连接酶E3A(UBE3A)的调控。前者可将翻译好的蛋白质靶向输送至蛋白酶。刺激发生6 h后,UBE3A合成并泛素化Arc/Arg3.1,致其降解[20]。故长时间刺激后,Arc/Arg3.1蛋白水平可恢复至基线水平。
2  Arc/Arg3.1在突触可塑性中的作用
      1949年,HEBB提出著名的Hebbian突触假说,即相互连接的两个神经元在经历同步放电活动后,它们之间的突触连接就会得到增强。这种由神经活动引起的神经元之间信息传递效能增强或减弱的现象被称为神经突触可塑性。
      Arc/Arg3.1不仅修饰突触结构,还可以调节突触强度。研究显示,LTP后期需要Arc/Arg3.1的参与。Arc/Arg3.1基因敲除小鼠接受高频刺激,在起始反应增强后出现稳步减弱的现象,而正常Arc/Arg3.1水平的急性调控中并未出现起始反应增强的现象,因此,它可能是终身Arc/Arg3.1表达缺陷所引起的后天性发育补偿。短时间Arc/Arg3.1水平的降低也可导致LTP后期的缺失。GUZOWSKI等[27]将Arc/Arg3.1反义寡核苷酸(ODNs)在LTP诱导前1.5 h注入大鼠海马,发现LTP的维持阶段缺失而早期阶段则不受影响。MESSAOUDI等在LTP诱导后2 h注射Arc/Arg3.1反义寡核苷酸可致LTP后期阶段永久缺失,并彻底消除BDNF诱导的LTP形式。关于Arc/Arg3.1作用于LTP的分子机制,有研究已经证实,Arc/Arg3.1可与钙-钙调蛋白依赖的蛋白激酶Ⅱ(Calcium/Calmodulin-dependent protein kinase Ⅱ,CaMKⅡ)发生相互作用,并可以增加其活性以及促进CaMKⅡ的神经元轴突生长。而CaMKⅡ是一个关键的信号蛋白分子,被称作“记忆的分子开关”,是LTP诱导与维持中的重要分子基础,在神经系统中具有非常重要的生物学作用[28]。Arc/Arg3.1作用于LTP的分子机制还包括细胞骨架动态变化的调节和树突棘形态的维持。Arc/Arg3.1定位于肌动蛋白细胞骨架,LTP可使致肌动蛋白聚合并增加其稳固性,反过来肌动蛋白稳定剂Jasplakinolide可防止Arc/Arg3.1基因受抑制所造成的LTP维持期缺失[29]
      Arc/Arg3.1除对LTP有关键的作用外,对于LTD来说亦必不可少。代谢型谷氨酸受体mGluR诱导的LTD需要Arc/Arg3.1发挥调节AMPA受体的内吞作用[21]。Arc/Arg3.1通过endophilin1和dynamin2促进AMPAR的胞吞作用从而降低了AMPAR介导的突触电流的幅度[30]。目前还不清楚Arc/Arg3.1作用于AMPA受体上GluA1还是 GluA2亚基,也有可能这两个亚基均受Arc/Arg3.1的调节。此外,Arc/Arg3.1还可以和Notch1发生共同免疫沉淀并激活Notch1受体。该受体在成熟神经元形态和突触可塑性的调节方面具有重要的作用。海马切片研究发现Notch1信号通路的阻断同时影响LTP和LTD[31]
3  Arc/Arg3.1在行为表达中的作用
      研究发现,抑制Arc/Arg3.1蛋白的表达破坏了LTP的维持,而未影响其诱导。实验动物经水迷宫的训练后,并未影响其信息的采集和短时程记忆,但却影响了其长时程记忆(long-term memory,LTM)。Arc/Arg3.1表达可以推断动物学习任务的完成情况。纹状体或海马中Arc/Arg3.1含量高的动物其逆反学习机动应答任务[32]和空间学习任务[33]完成得更快。然而,有研究观察到海马中表达较高水平Arc/Arg3.1动物学习杠杆的速度更慢[34]。这种明显的差异可能是由于后一种学习并不依赖于海马。还有一项研究发现,过度杠杆训练的动物其众多脑区的Arc/Arg3.1表达水平均低于新训练的动物[35]。虽然Arc/Arg3.1水平和学习能力之间的确切关系尚未明了,但Arc/Arg3.1的精确调制显然有助于众多形式的学习和行为反应。
4  Arc/Arg3.1与阿尔茨海默病
      AD正日益被称为“synaptopathy”[36],反映了疾病的发展过程中突触的丢失或损伤,从而产生特定神经回路功能的退化和随之发生的神经网络活动的减少[37]。AD早期病理研究主要集中于淀粉样前体蛋白通路及其蛋白裂解产物Aβ形成的斑块。近几年来,越来越多的研究表明,神经毒性Aβ低聚体沉积可干扰突触功能,而突触功能与Arc/Arg3.1密切相关。
      LANDGREN等调查人类Arc/Arg3.1遗传变异性和罹患AD的风险,对健康组成员进行Arc/Arg3.1测序发现,SNP+2852(G/A)与AD的患病风险、简易精神状态量表(MMSE)分数、脑脊液(CSF)的生物标志物、总tau(T-tau蛋白)、过度磷酸化的tau181和Aβ142有关。且新发现的3’-UTR SNP+2852(A/G)中的AA基因型与AD发病风险降低相关。
      GINSBERG等[38]发现AD 患者出现神经元纤维缠结的CA1区,其Arc/Arg3.1 mRNA水平较正常组明显下降,而WU等[39]尸检AD患者的大脑发现额中回Arc/Arg3.1蛋白水平出现极大的上调。在动物模型的研究中,ECHEVERRIA等[40]以人工合成Aβ建造AD小鼠模型,在原代皮质神经元的培养中发现Arc/Arg3.1表达水平下降。以人工合成Aβ建造大鼠模型,WANG等[41]和CHEN等[42]均在原代培养的皮质神经元中观测到Arc/Arg3.1表达的下调,而LACOR等[43]却在原代培养的海马神经元中发现Arc/Arg3.1表达上升。WEGENAST-BRAUN等[44]利用多种转基因小鼠模型研究发现,年轻和年老的小鼠海马和皮质中Arc/Arg3.1的表达均下降,这与DICKEY等[45-46]的研究一致。有趣的是,PALOP等[47]在4~7月龄的小鼠海马中同时观测到Arc/Arg3.1表达上升和下降的现象。可见,目前研究者对AD患者体内Arc/Arg3.1表达的变化趋势观点不一,但可以确定的是,AD患者大脑神经元中Arc/Arg3.1表达的失调干扰了正常的神经生理活动,参与了AD的发病。RUDINSKIY等[48]提出,Arc/Arg3.1 的表达模式影响了神经系统对行为体验的反应,也干扰了行为体验的生理性增强。破坏Arc/Arg3.1表达模式出现的斑块沉积干扰神经元网络的集成,最终导致AD的突触功能受损。
      Arc/Arg3.1不仅为AD的研究打开了一扇窗,也为AD的其他发病机制假说提供了一个切入点。神经炎症与AD等众多神经病理性疾病有关,且可以由活化的小胶质细胞检测。早期AD 病人便可在涉及学习和记忆的脑区观察到小胶质细胞发生最大程度的激活。ROSI等[49]在试验性炎症的诱导下观察海马中活动诱导性即早基因Arc/Arg3.1的表达。脑室中注入脂多糖的大鼠齿状回和CA3区Arc/Arg3.1和OX-6(主要组织相容性复合体Ⅱ类抗原)免疫标记以及Arc/Arg3.1荧光原位杂交发现激活的小胶质细胞以及Arc/Arg3.1的表达上升。行为诱导性Arc/Arg3.1表达的改变只发生在有小胶质细胞激活的区域(OX-6免疫激活),表明在学习和突触可塑性方面,神经炎症可能会影响神经活动与大分子物质合成的耦合。由神经炎症引发的Arc/Arg3.1表达的活动依赖性改变,可能与AD患者认知功能缺陷有关。
5  结语
      AD是慢性进行性中枢神经系统变性病导致的痴呆,是痴呆最常见的病因和最常见的老年期痴呆。AD以渐进性记忆障碍、认知功能障碍、人格改变以及语言障碍等神经精神症状为特征,严重影响了患者和家人的生活及工作。Arc/Arg3.1作为一个即刻早期基因,在突触重塑中作用显著,而突触可塑性与LTP有关,LTP是学习与记忆的分子基础,因此,Arc/Arg3.1与学习记忆等认知功能关系密切。生理情况下,Arc/Arg3.1介导正常学习记忆功能的建立,而在病理情况下,如AD患者中Arc/Arg3.1的表达如何以及其变化如何影响学习记忆过程,有待进一步探讨。
6  参考文献
[1]  DOROSTKAR M M,HERMS J.Arc illuminates Alzheimer's pathophysiology[J].Nature Neurosci,2012,15(10):1 323-1 325.
[2]  KRAFT A W,BAUER A Q,CULVER J P,et al.Sensory deprivation after focal ischemia in mice accelerates brain remapping and improves functional recovery through Arc-dependent synaptic plasticity[J].Sci Transl Med,2018,10(426).(pii):10/426/eaag1328.
[3]  SHANKAR G M,LI S,MEHTA T H,et al.Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory[J].Nat Med,2008,14(8):837-842.
[4]  LAMBERT M P,BARLOW A K,CHROMY B A,et al.Diffusible,nonfibrillar ligands derived from Abet al-42 are potent central nervous system neurotoxins[J].Proc Natl Acad Sci U S A,1998,95(11):6 448-6 453.
[5]  BALDUCCI C,BEEG M,STRAVALACI M,et al.Synthetic amyloid-beta oligomers impair long-term memory independently of cellular prion protein[J].Proc Natl Acad Sci U S A,2010,107(5):2 295-2 300.
[6]  GASPAROVA Z,STARA V,STOLC S.Effect of antioxidants on functional recovery after in vitro-induced ischemia and long-term potentiation recorded in the pyramidal layer of the CA1 area of rat hippocampus[J].Gen Physiol Biophys,2013,361(6 407):31-39.
[7]  NIKOLAIENKO O,PATIL S,ERIKSEN M S,et al.Arc protein:a flexible hub for synaptic plasticity and cognition[J].Semin Cell Dev,Biol,2017,7(17):30 343-30 349.
[8]  MABB A M,EHLERS M D.Arc ubiquitination in synaptic plasticity[J].Semin Cell Dev Biol,2017.pii:S1084-9521(16)30502-X.
[9]  JANKOWSKY J L,SLUNT H H,RATOVITSKI T,et al.Co-expression of multiple transgenes in mouse CNS:a comparison of strategies[J].Biomol Eng,2001,17(6):157-165.
[10]  LYFORD G L,YAMAGATA K,KAUFMANN W E,et al.Arc,a growth factor andactivity-regulated gene,encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites[J].Neuron,1995,14(2):433-445.
[11]  MATTALIANO M D,MONTANA E S,PARISKY K M,et al.The Drosophila ARC homolog regulates behavioral responses to starvation[J].Mol Cell Neurosci,2007,36(2):211-221.
[12]  MIYASHITA T,KUBIK S,LEWANDOWSKI G,et al.Networks of neurons,networks of genes:an integrated view of memory consolidation[J].Neurobiol Learn Mem,2008,89(3):269-284.
[13]  LINK W,KONIETZKO U,KAUSELMANN G,et al.Somatodendritic expression of an immediate early gene is regulated by synaptic activity[J].Proc Natl Acad Sci U S A,1995,92(12):5 734-5 738.
[14]  RAMIREZ-AMAYA V,VAZDARJANOVA A,MIKHAEL D,et al.Spatial exploration-induced Arc mRNA and protein expression:evidence for selective,network-specific reactivation[J].J Neurosci,2005,25(7):1 761-1 768.
[15]  PINTCHOVSKI S A,PEEBLES C L,KIM H J,et al.The serum response factor and a putative novel transcription factor regulate expression of the immediate-early gene Arc/Arg3.1 in neurons[J].J Neurosci,2009,29(5):1 525-1 537.
[16]  YILMAZ-RASTODER E,MIYAMAE T,BRAUN A E,et al.LTP-and LTD-inducing stimulations cause opposite changes in arc/arg3.1 mRNA level in hippocampal area CA1 in vivo[J].Hippocampus,2011,21(12):1 290-1 301.
[17]  PARK S,PARK J M,KIM S,et al.Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD[J].Neuron,2008,59(1):70-83.
[18]  PASTUZYN E D,SHEPHERD J D.Activity-Depen-dent Arc Expression and Homeostatic Synaptic Plasticity Are Altered in Neurons from a Mouse Model of Angelman Syndrome[J].Front Mol Neurosci,2017,10:234.
[19]  SAHA R N,WISSINK E M,BAILEY E R,et al.Rapid activity-induced transcription of Arc and other IEGs relies on poised RNA polymerase II[J].Nat Neurosci,2011,14(7):848-856.
[20]  RAO V R,PINTCHOVSKI S A,CHIN J,et al.AMPA receptors regulate transcriptionof the plasticity-related immediate-early gene Arc[J].Nat Neurosci,2006,9(7):887-895.
[21]  WAUNG M W,PFEIFFER B E,NOSYREVA E D,et al.Rapid translation of Arc/Arg3.1 selectively mediates mGluR-dependent LTD through persistent increases in AMPAR endocytosis rate[J].Neuron,2008,59(1):84-97.
[22]  TEBER I,KOHLING R,SPECKMANN E J,et al.Muscarinic acetylcholine receptor stimulation induces expression of the activity-regulated cytoskeleton-associated gene (ARC)[J].Brain Res Mol Brain Res,2004,121(1/2):131-136.
[23]  STEWARD O,WORLEY P F.Selective targeting of newly synthesized Arc mRNA to active synapses requires NMDA receptor activation[J].Neuron,2001,30(1):227-240.
[24]  POSERN G,TREISMAN R.Actin' together:serum response factor,its cofactors and the link to signal transduction[J].Trends Cell Biol,2006,16(11):588-596.
[25]  BLOOMER W A,VANDONGEN H M,VANDONGEN A M.Arc/Arg3.1 translation is controlled by conver-gent N-methyl-D-aspartate and Gs-coupled receptor signaling pathways[J].J Biol Chem,2008,283(1):582-592.
[26]  PANJA D,DAGYTE G,BIDINOSTI M,et al.Novel translational control in Arc-dependent long term potentiation consolidation in vivo[J].J Biol Chem,2009,284(46):31 498-31 511.
[27]  GUZOWSKI J F,LYFORD G L,STEVENSON G D,et al.Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the main-tenance of long-term potentiation and the consolidation of long-term memory[J].J Neurosci,2000,20(11):3 993-4 001.
[28]  MESSAOUDI E,KANHEMA T,SOULE J,et al.Sustained Arc/Arg3.1 synthesis controls long-term potentiation consolidation through regulation of local actin polymerization in the dentate gyrus in vivo[J].J Neurosci,2007,27(39):10 445-10 455.
[29]  SHEPHERD J D,BEAR M F.New views of Arc,a master regulator of synaptic plasticity[J].Nat Neurosci,2011,14(3):279-284.
[30]  CHOWDHURY S,SHEPHERD J D,OKUNO H,et al.Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking[J].Neuron,2006,52(3):445-459.
[31]  ALBERI L,LIU S,WANG Y,et al.Activity-induced Notch signaling in neurons requires Arc/Arg3.1 and is essential for synaptic plasticity in hippocampal networks[J].Neuron,2011,69(3):437-444.
[32]  DABERKOW D P,RIEDY M D,KESNER R P,et al.Arc mRNA induction in striatal efferent neurons associated with response learning[J].Eur J Neurosci,2007,26(1):228-241.
[33]  GUZOWSKI J F,SETLOW B,WAGNER E K,et al.Experience-dependent gene expression in the rat hippocampus after spatial learning:a comparison of the immediate-early genes Arc,c-fos,and zif268[J].J Neurosci,2001,21(14):5 089-5 098.
[34]  KELLY M P,DEADWYLER S A.Experience-depen-dent regulation of the immediate-early gene arc differs across brain regions[J].J Neurosci,2003,23(16):6 443-6 451.
[35]  KELLY M P,DEADWYLER S A.Acquisition of a novel behavior induces higher levels of Arc mRNA than does overtrained performance[J].Neuroscience,2002,110(4):617-626.
[36]  Kerrigan T L,Randall A D.A new player in the ”synaptopathy” of Alzheimer's disease-arc/arg 3.1[J].Front Neurol,2013,4:9.
[37]  LANDGREN S,VON OTTER M,PALMER M S,et al.A novel ARC gene polymorphism is associated with reduced risk of Alzheimer's disease[J].J Neural Transm,2012,119(7):833-842.
[38]  GINSBERG S D,HEMBY S E,LEE V M,et al.Expression profile of transcripts in Alzheimer's disease tangle-bearing CA1 neurons[J].Ann Neurol,2000,48(1):77-87.
[39]  WU J,PETRALIA R S,KURUSHIMA H,et al.Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent beta-amyloid generation[J].Cell,2011,147(3):615-628.
[40]  ECHEVERRIA V,BERMAN D E,ARANCIO O.Oligomers of beta-amyloid peptide inhibit BDNF-induced arc expression in cultured cortical Neurons[J].Curr Alzheimer Res,2007,4(5):518-521.
[41]  WANG K H,MAJEWSKA A,SCHUMMERS J,et al.In vivo two-photon imaging reveals a role of arc in enhancing orientation specificity in visual cortex[J].Cell,2006,126(2):389-402.
[42]  CHEN T J,WANG D C,CHEN S S.Amyloid-beta interrupts the PI3K-Akt-mTOR signalingpathway that could be involved in brain-derived neurotrophic factor-induced Arc expression in rat cortical neurons[J].J Neurosci Res,2009,87(10):2 297-2 307.
[43]  LACOR P N,BUNIEL M C,CHANG L,et al.Synaptic targeting by Alzheimer's-related amyloid beta oligomers[J].J Neurosci,2004,24(45):10 191-10 200.
[44]  WEGENAST-BRAUN B M,FULGENCIO M A,EICKE D,et al.Independent effects of intra-and extracellular Abeta on learning-related gene expression[J].Am J Pathol,2009,175(1):271-282.
[45]  DICKEY C A,GORDON M N,MASON J E,et al.Amyloid suppresses induction of genes critical for memory consolidation in APP+PS1 transgenic mice[J].J Neurochem,2004,88(2):434-442.
[46]  DICKEY C A,LORING J F,MONTGOMERY J,et al.Selectively reduced expression of synaptic plasticity-related genes in amyloid precursor protein + presenilin-1 transgenic mice[J].J Neurosci,2003,23(12):5 219-5 226.
[47]  PALOP J J,CHIN J,BIEN-LY N,et al.Vulnerability of dentate granule cells to disruption of arc expression in human amyloid precursor protein transgenic mice[J].J Neurosci,2005,25(42):9 686-9 693.
[48]  RUDINSKIY N,HAWKES J M,BETENSKY R A,et al.Orchestrated experience-driven Arc responses are disrupted in a mouse model of Alzheimer's disease[J].Nat Neurosci,2012,15(10):1 422-1 429.
[49]  ROSI S,RAMIREZ-AMAYA V,VAZDARJANOVA A,et al.Neuroinflammation alters the hippocampal pattern of behaviorally induced Arc expression[J].J Neurosci,2005,25(3):723-731.
(收稿2018-02-09  修回2018-02-27)
本文编辑:夏保军
本文引用信息:杨承源,杨惠林,许丽珍,朱奕潼.即刻早期基因Arc/Arg3.1的表达及与阿尔茨海默病关系的研究进展[J].中国实用神经疾病杂志,2018,21(3):331-335.
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