Nogo-A及其受体在阿尔茨海默病中的作用

doi:10.16098/j.issn.0529-1356.2018.04.023

摘要/Abstract

摘要：

Nogo-A是一种重要的髓鞘相关生长抑制因子，在成体动物中枢神经系统损伤再生中发挥了关键的抑制作用。近年来许多研究表明， Nogo-A及其受体NgR可以影响淀粉样蛋白Aβ的代谢，其下游的ROCK激酶可以影响Aβ、tau蛋白的水平以及血脑屏障的通透性，这些均提示Nogo-A及其受体与阿尔茨海默病（AD）的发病机制有着密切的联系。此外，最近的研究还发现了Nogo-A的另外两种受体PirB和S1PR2，可能为Nogo-A在神经系统疾病中的作用提供新的研究方向。我们将着重阐释Nogo-A及其受体的基本结构和功能的新发现，以及其在AD中的作用等方面的最新研究进展。

关键词: Nogo-A, 阿尔茨海默病, 神经退行性疾病

Abstract:

Nogo-A is an important myelin associated inhibitory factor, which creates a critical barrier to the central nervous system regeneration after injury. Recent research shows that Nogo-A/Nogo-A receptors can affect the metabolism of amyloid-β-protein (Aβ), and its downstream ROCK kinase. It can modulate the level of Aβ and tau protein, as well as the permeability of blood brain barrier. These findings suggest that Nogo-A/Nogo-A receptors have a close relationship with Alzheimer’s disease (AD). Moreover, two new receptors of Nogo-A, PirB and S1PR2, have been identified recently. The identification of these two receptors may provide new insight into the mechanism of Nogo-A involving in the progress of central nervous diseases. we focuses on the up-to-date knowledge of the basic structure and function of Nogo-A/Nogo-A receptors and their role in AD pathogenesis.

Key words: Nogo-A, Alzheimer’s disease, Neurodegenerative disease

王兆伦张艳王君. Nogo-A及其受体在阿尔茨海默病中的作用[J]. 解剖学报, 2018, 49(4): 549-555.

WANG Zhao-lun ZHANG Yan WANG Jun. Role of Nogo-A and Nogo-A receptors in Alzheimer’s disease[J]. Acta Anatomica Sinica, 2018, 49(4): 549-555.

参考文献

［1］ Oertle T, van der Haar ME, Bandtlow CE, et al. Nogo-A inhibits neurite outgrowth and cell spreading with three discrete regions［J］. J Neurosci, 2003, 23(13): 5393-5406.

［2］ Schwab ME. Functions of Nogo proteins and their receptors in the nervous system［J］. Nat Rev Neurosci, 2010, 11(12): 799-811.

［3］ Bella J, Hindle KL, McEwan PA, et al. The leucine-rich repeat structure［J］. Cell Mol Life Sci, 2008, 65(15): 2307-2333.

［4］ Yamashita T, Higuchi H, Tohyama M. The p75 receptor transduces the signal from myelin-associated glycoprotein to Rho［J］. J Cell Biol, 2002, 157(4): 565-570.

［5］ Montani L, Gerrits B, Gehrig P, et al. Neuronal Nogo-A modulates growth cone motility via Rho-GTP/LIMK1/cofilin in the unlesioned adult nervous system［J］. J Biol Chem, 2009, 284(16): 10793-10807.

［6］ Atwal JK, Pinkston-Gosse J, Syken J, et al. PirB is a functional receptor for myelin inhibitors of axonal regeneration［J］. Science, 2008, 322(5903): 967-970.

［7］ Haruka M, Shota E, Eiji K, et al. Differential but competitive binding of Nogo protein and class i major histocompatibility complex (MHCI) to the PIR-B ectodomain provides an inhibition of cells［J］. J Biol Chem, 2011, 286(29): 25739-25747.

［8］ Yuki F, Shota E, Toshiyuki T, et al. Myelin suppresses axon regeneration by PIR-B/SHP-mediated inhibition of Trk activity［J］. EMBO J, 2011, 30(7): 1389-1401.

［9］ Dickson HM, Jonathan Z, Huanqing Z, et al. POSH is an intracellular signal transducer for the axon outgrowth inhibitor Nogo66［J］. J Neurosci, 2010, 30(40): 13319-13325.

［10］ Fujita Y, Takashima R, Endo S, et al. The p75 receptor mediates axon growth inhibition through an association with PIR-B［J］. Cell Death Dis, 2011, 2(9): e198.

［11］ Kempf A, Tews B, Arzt ME, et al. The sphingolipid receptor S1PR2 is a receptor for Nogo-a repressing synaptic plasticity［J］. PLoS Biol, 2014, 12(1): e1001763.

［12］ Joset A, Dodd DA, Halegoua S, et al. Pincher-generated Nogo-A endosomes mediate growth cone collapse and retrograde signaling［J］. J Cell Biol, 2010, 188(2): 271-285.

［13］ Xiong NX, Zhao HY, Zhang FCh, et al. The role of calcium in Nogo-A inhibiting axonal outgrowth［J］. Acta Anatomica Sinica, 2005, 36(6): 582-585.(in Chinese)

熊南翔, 赵洪洋, 张方成, 等. 钙离子参与Nogo-A抑制轴突生长的作用［J］. 解剖学报, 2005, 36(6): 582-585.

［14］ Hannila SS, Filbin MT. The role of cyclic AMP signaling in promoting axonal regeneration after spinal cord injury［J］. Exp Neurol, 2008, 209(2): 321-332.

［15］ Cheng XP, Liu HL, Song ChJ, et al. Immunohistochemical localization of Nogo-A in the neurons of the brain of adult rat［J］. Acta Anatomica Sinica, 2005, 36(5): 465-470. (in Chinese)

程希平, 刘惠玲, 宋朝君, et al. Nogo-A在成年大鼠脑内神经元的分布［J］. 解剖学报, 2005, 36(5): 465-470.

［16］ Zheng ChX, Shen JX, Jin WL, et al. Changes in Nogo-A distribution in hippocampal neurons during growth in vitro［J］. Acta Anatomica Sinica, 2004, 35(4): 350-353. (in Chinese)

郑春霞, 申军现, 金卫林, et al. 体外培养海马神经元生长过程中Nogo-A分布的变化［J］. 解剖学报, 2004, 35(4): 350-353.

［17］ McGee AW, Yang Y, Fischer QS, et al. Experience-driven plasticity of visual cortex limited by myelin and Nogo receptor［J］. Science, 2005, 309(5744): 2222-2226.

［18］ Akbik FV, Bhagat SM, Patel PR, et al. Anatomical plasticity of adult brain is titrated by Nogo Receptor 1［J］. Neuron, 2013, 77(5): 859-866.

［19］ Jitsuki S, Nakajima W, Takemoto K, et al. Nogo receptor signaling restricts adult neural plasticity by limiting synaptic AMPA receptor delivery［J］. Cereb Cortex, 2016, 26(1): 427-439.

［20］ Delekate A, Zagrebelsky M, Kramer S, et al. NogoA restricts synaptic plasticity in the adult hippocampus on a fast time scale［J］. Proc Natl Acad Sci USA, 2011, 108(6): 2569-2574.

［21］ Lee H, Raiker SJ, Venkatesh K, et al. Synaptic function for the Nogo-66 receptor NgR1: regulation of dendritic spine morphology and activity-dependent synaptic strength［J］. J Neurosci, 2008, 28(11): 2753-2765.

［22］ Karlen A, Karlsson TE, Mattsson A, et al. Nogo receptor 1 regulates formation of lasting memories［J］. Proc Natl Acad Sci USA, 2009, 106(48): 20476-20481.

［23］ Raiker SJ, Lee H, Baldwin KT, et al. Oligodendrocyte-myelin glycoprotein and Nogo negatively regulate activity-dependent synaptic plasticity［J］. J Neurosci, 2010, 30(37): 12432-12445.

［24］ Tews B, Schonig K, Arzt ME, et al. Synthetic microRNA-mediated downregulation of Nogo-A in transgenic rats reveals its role as regulator of synaptic plasticity and cognitive function［J］. Proc Natl Acad Sci USA, 2013, 110(16): 6583-6588.

［25］ Zemmar A, Weinmann O, Kellner Y, et al. Neutralization of Nogo-A enhances synaptic plasticity in the rodent motor cortex and improves motor learning in vivo［J］. J Neurosci, 2014, 34(26): 8685-8698.

［26］ He W, Lu Y, Qahwash Ⅰ, et al. Reticulon family members modulate BACE1 activity and amyloid-beta peptide generation［J］. Nat Med, 2004, 10(9): 959-965.

［27］ He W, Hu X, Shi Q, et al. Mapping of interaction domains mediating binding between BACE1 and RTN/Nogo proteins［J］. J Mol Biol, 2006, 363(3): 625634.

［28］ Kume H, Murayama KS, Araki W. The two-hydrophobic domain tertiary structure of reticulon proteins is critical for modulation of beta-secretase BACE1［J］. J Neurosci Res, 2009, 87(13): 2963-2972.

［29］ Shi Q, Prior M, He W, et al. Reduced amyloid deposition in mice overexpressing RTN3 is adversely affected by preformed dystrophic neurites［J］. J Neurosci, 2009, 29(29): 9163-9173.

［30］ Hu X, Shi Q, Zhou X, et al. Transgenic mice overexpressing reticulon 3 develop neuritic abnormalities［J］. EMBO J, 2007, 26(11): 2755-2767.

［31］ Masliah E, Xie F, Dayan S, et al. Genetic deletion of Nogo/Rtn4 ameliorates behavioral and neuropathological outcomes in amyloid precursor protein transgenic mice［J］. Neuroscience, 2010, 169(1): 488-494.

［32］ Prior M, Shi Q, Hu X, et al. RTN/Nogo in forming Alzheimer’s neuritic plaques［J］. Neurosci Biobehav Rev, 2010, 34(8): 1201-1206.

［33］ Bros-Facer Ⅴ, Krull D, Taylor A, et al. Treatment with an antibody directed against Nogo-A delays disease progression in the SOD1G93A mouse model of Amyotrophic lateral sclerosis［J］. Hum Mol Genet, 2014, 23(16): 4187-4200.

［34］ Cheng X, Wu J, Geng M, et al. Role of synaptic activity in the regulation of amyloid beta levels in Alzheimer’s disease［J］. Neurobiol Aging, 2014, 35(6): 1217-1232.

［35］ Park JH, Gimbel DA, GrandPre T, et al. Alzheimer precursor protein interaction with the Nogo-66 receptor reduces amyloid-beta plaque deposition［J］. J Neurosci, 2006, 26(5): 1386-1395.

［36］ Deane R, Du Yan S, Submamaryan RK, et al. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain［J］. Nat Med, 2003, 9(7): 907-913.

［37］ Park JH, Widi GA, Gimbel DA, et al. Subcutaneous Nogo receptor removes brain amyloid-beta and improves spatial memory in Alzheimer’s transgenic mice［J］. J Neurosci, 2006, 26(51): 13279-13286.

［38］ Zhou X, Hu X, He W, et al. Interaction between amyloid precursor protein and Nogo receptors regulates amyloid deposition［J］. FASEB J, 2011, 25(9): 3146-3156.

［39］ Kim T, Vidal GS, Djurisic M, et al. Human LilrB2 is a beta-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer’s model［J］. Science, 2013, 341(6152): 1399-1404.

［40］ Zhou Y, Su Y, Li B, et al. Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Abeta42 by inhibiting Rho［J］. Science, 2003, 302(5648): 1215-1217.

［41］ Pedrini S, Carter TL, Prendergast G, et al. Modulation of Statin-Activated Shedding of Alzheimer APP Ectodomain by ROCK［J］. PLoS Med, 2005, 2(1): e18.

［42］ Shi J, Wu X, Surma M, et al. Distinct roles for ROCK1 and ROCK2 in the regulation of cell detachment［J］. Cell Death Dis, 2013, 4(2): e483.

［43］ Herskowitz JH, Feng Y, Mattheyses AL, et al. Pharmacologic inhibition of ROCK2 suppresses amyloid-β production in an Alzheimer’s disease mouse model［J］. J Neurosci, 2013, 33(49): 19086-19098.

［44］ Henderson BW, Gentry EG, Rush T, et al. Rho-associated protein kinase 1 (ROCK1) is increased in Alzheimer’s disease and ROCK1 depletion reduces amyloid-β levels in brain［J］. J Neurochem, 2016, 138(4):525-531.

［45］ Hu YB, Zou Y, Huang Y, et al. ROCK1 is associated with Alzheimer’s disease-specific plaques, as well as enhances autophagosome formation but not autophagic Aβ clearance［J］. Front Cell Neurosci, 2016, 10:253.

［46］ Gentry EG, Henderson BW, Arrant AE, et al. Rho kinase inhibition as a therapeutic for progressive supranuclear palsy and corticobasal degeneration［J］. J Neurosci, 2016, 36(4): 1316-1323.

［47］ Park JC, Baik SH, Han SH, et al. Annexin A1 restores A beta(1-42)-induced bloodbrain barrier disruption through the inhibition of RhoA-ROCK signaling pathway［J］. Aging Cell, 2017, 16(1): 149-161.

[1]	马婷婷陈建红刘爱翠李海宁. 抑制lncRNA TUG1下调核苷酸结合寡聚结构域样受体蛋白1炎症小体在延缓阿尔茨海默病进展的作用 [J]. 解剖学报, 2024, 55(1): 32-42.
[2]	王文娟丁雨桐苏昊任捷孙艳荣王涵菲陆嘉莉张林倩白钰秦丽华. 低雌激素状态下大鼠海马及纹状体Nogo-A的表达变化[J]. 解剖学报, 2023, 54(6): 620-627.
[3]	王宏方耿丹丹张润姣刘清李一博王磊. 环状RNA在阿尔茨海默病中的作用及研究进展[J]. 解剖学报, 2023, 54(4): 490-494.
[4]	侯翌葳杨宇王博段英涛姚宏波. 普兰林肽对5×FAD小鼠和WT小鼠认知行为及脑和视网膜β淀粉样蛋白6E10、炎症因子和神经细胞形态的影响[J]. 解剖学报, 2023, 54(3): 283-288.
[5]	陈搏雨江锦祥张家玮杨莉. APP/PS1小鼠嗅球神经元的早期树突分支和长度及钾-氯离子共运转体2蛋白表达异常[J]. 解剖学报, 2023, 54(2): 127-133.
[6]	许琳刘晓丽陈争珍闻彩云李昌盛李如画陈黛茜陈成春. 阿尔茨海默病患者静息态下脑局部活动的多指标分析[J]. 解剖学报, 2023, 54(1): 75-81.
[7]	胡耀文孙艳荣孙昊哲王文娟张苏欣秦丽华. Nogo蛋白与心肌纤维化关系的研究进展[J]. 解剖学报, 2022, 53(5): 674-679.
[8]	郎尉雅张春梅张羽镝刘忠锦衣同辉张可爽张海燕. 鹿茸多肽在阿尔茨海默病模型小鼠中抗氧化应激的作用机制[J]. 解剖学报, 2022, 53(4): 432-439.
[9]	唐伟博刘丽申景岭. 核蛋白TAR DNA/RNA结合蛋白43与小鼠肌萎缩侧索硬化症的关系[J]. 解剖学报, 2022, 53(4): 440-446.
[10]	刘忠锦张春梅张羽镝衣同辉郎尉雅张海燕. 鹿茸多肽对APP/PS1双转基因小鼠Rho/ROCK通路的影响[J]. 解剖学报, 2022, 53(2): 190-195.
[11]	陈小平邢彦伟闫朝霞常红叶陈贝贝范文娟 . 阿尔茨海默病合并2型糖尿病模型小鼠海马血管损伤与认知改变[J]. 解剖学报, 2021, 52(6): 863-869.
[12]	马冬雪高维娟贺小平许力军刘亚磊董贤慧. 淫黄葛复合剂对阿尔茨海默病小鼠行为学和海马解聚素金属蛋白酶10表达的影响[J]. 解剖学报, 2020, 51(6): 821-826.
[13]	郎尉雅刘忠锦张海燕孙丽慧朱坤杰. 表没食子儿茶素没食子酸酯对APP/PS1双转基因小鼠神经元突触可塑性和神经细胞黏附分子表达的影响[J]. 解剖学报, 2020, 51(4): 495-501.
[14]	胡启国刘怀存陈玲赵妍王君 . 大鼠背根神经节中的Nogo-A蛋白促进微管聚合和炎症热痛觉敏化的发生[J]. 解剖学报, 2019, 50(5): 549-553.
[15]	苏翔张臻杨霖璟裘益辉宋成龙陈娟燕宋水江 . 粒细胞集落刺激因子改善阿尔茨海默病模型大鼠学习记忆功能及抗炎作用机制[J]. 解剖学报, 2019, 50(1): 29-34.