ACM  >> Vol. 8 No. 1 (February 2018)

    阿尔兹海默病发病机理概述及治疗策略展望
    An Overview of Alzheimer’s Disease Pathogenesis and the Outlook for Its Treatment

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作者:  

王天佐,张 莹,薛真真,朱启顺:云南大学生命科学院,云南 昆明

关键词:
阿尔兹海默病氧化应激神经炎症神经原纤维缠结AD Oxidative Stress Neuroinflammation Neurofibrillary Tangles

摘要:

阿尔兹海默病(Alzheimer’s disease, AD)是最常见的一类的神经退行性疾病,也是最常见的一类痴呆病,高发于老龄群体。AD临床症状包括语言障碍、记忆丢失、易怒、抑郁等认知功能障碍及行为异常;AD病理特征主要包括神经元外β-淀粉样蛋白(β-amyloid, Aβ)沉积形成的老年斑(senile plaques, SPs)和神经元内Tau蛋白过度磷酸化形成的神经原纤维缠结(neurofibrillary tangles, NFTs)、神经元丢失等。尽管AD发病机理至今尚不清楚,但越来越多的证据表明Aβ与AD病理紧密相关,本文综述Aβ诱导的氧化应激、炎症反应及神经元调亡与AD病理的相关性,以期为AD新药研发提供新的思路。

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and its prevalence is closely related to aging, and also the most common cause of dementia. AD is clinically characterized by cognitive deficits and behavioral disorders like language disorders, memory loss, agitation and depression. AD is pathologically characterized by senile plaques (SPs) composed of β-amyloid (Aβ), neurofibrillary tangles (NFTs) caused by hyperphosphorylated Tau proteins, and neuronal loss. AD pathogenesis is not well understood yet, but a body of evidence shows that Aβ plays a critical role in AD pathology. In this paper, we review the role of Aβ-induced oxidative stress, neuroinflammation and neuronal apoptosis in AD pathology, aiming to provide new ideas for the development of new therapeutic drugs against AD.

1. 阿尔茨海默病

阿尔兹海默病(Alzheimer’s disease, AD)是最常见的一类的神经退行性疾病,其发病与衰老紧密相关 [1] ;AD高发于老龄群体,也是最常见的一类痴呆病 [2] ,其临床表现包括语言障碍、记忆丢失、易怒及抑郁等认知及行为方面的异常 [3] [4] ,其病理特征主要包括神经元外β-淀粉样蛋白(β-amyloid, Aβ)沉积形成的老年斑(senile plaque, SP)、神经元内Tau蛋白过度磷酸化形成的神经原纤维缠结(neurofibrillary tangles, NFT)及神经元丢失 [5] [6] 。越来越多的证据表明Aβ诱导的氧化应激(oxidative stress)、炎症反应(inflammation)及神经元调亡(apoptosis)与AD病理紧密相关。

2. Aβ与氧化应激

氧化应激是指因机体氧化-抗氧化内稳态(oxidant-antioxidant homeostasis)受损,导致自由基过量积累,对机体造成氧化损伤的现象;氧化应激可导致生物大分子脂质、蛋白质、DNA及RNA的过氧化损伤 [7] [8] 。越来越多的研究结果显示,氧化应激与AD发病密切相关 [9] [10] [11] 。Aβ是由39~43个氨基酸残基组成的多肽,是老年斑的主要组成部分 [12] ;诸多研究表明,Aβ沉积可诱导氧化应激反应、引起神经元凋亡 [13] [14] [15] ,Aβ诱导的氧化应激在AD发病中起关键作用 [16] [17] 。研究表明,Aβ可显著提高AD老鼠脑组织脂质过氧化水平,致使NO、MDA水平显著上升 [18] 。Montine T等的研究显示,Aβ可促进自由基的生成,损伤学习能力和记忆能力 [19] ;Soodi M等的研究显示,大鼠海马区注射Aβ可显著提高大脑脂质过氧化水平,导致大鼠认知功能损伤 [20] ;Hayeon J等的研究显示,Aβ可显著提高细胞活性氧簇(reactive oxygen species, ROS)的生成水平,促进细胞染色质固缩和细胞凋亡 [21] ;而使用抗氧化剂可改善Aβ诱导的氧化损伤和认知功能损伤 [22] [23] [24] 。另有研究证明,Aβ寡聚物能降质膜的流动性,质膜流动性的下降反过来又刺激Aβ的生成 [25] ,Aβ聚集形成的可溶性聚集体可伸入质膜,促进ROS的生成,继而加剧氧化应激反应 [26] [27] ,ROS对生物大分子DNA、蛋白质、脂质以及细胞内小分子的氧化,导致细胞损伤 [27] [28] 。研究显示,线粒体功能障碍与神经退行性病变紧密相关,且神经元对线粒体功能障碍和氧化应激非常敏感 [29] 。ROS是线粒体电子传递链(electron transport chain)的主要中间产物,如过氧化氢和羟自由基,在正常生理状态下,ROS具有维持内稳态、调节与细胞生长、增殖、存活相关的信号转导的功能 [30] ,线粒体功能障碍可导致ROS过度生成 [31] ,ROS过度生成进一步加剧氧化应激对线粒的损伤,破坏电子传递链、降低ATP合成,形成“ROS-线粒体损伤-ROS”恶性循环 [32] 。大脑是高度耗能器官,耗氧量达机体总量的20%,且大脑中多不饱和脂肪酸的含量高于其他器官,这使得大脑更易遭受氧化应激损伤 [33] 。因此,Aβ诱导的氧化应激已被广泛认为是导致AD重要因素之一 [34] 。Aβ的生成源自β-分泌酶(β-secretase,BACE1)对Aβ前体蛋白(amyloid precursor protein, APP)的酶切,因此BACE1被认为是Aβ生成的关键因素 [35] ,抑制BACE1也因此被认为是治疗AD的关键环节 [36] [37] 。综上所述,本文推测Aβ可能通过与质膜相互作用诱导氧化应激,对线粒体及脂质、核酸、蛋白质等生物大分子造成氧化损伤,最终引起神经元凋亡。因此BACE1和Aβ可作为AD的重要治疗靶点(如图1)。

3. Aβ与神经炎症

研究认为,神经炎症(neuroinflammation)是AD的病理特征之一 [38] ,神经炎症是Aβ诱导神经元死亡的重要介导因素之一,是除氧化应激外诱导AD病理的另一重要因素 [39] ,越来越多的证据表明,Aβ诱导的炎症反应是Aβ神经毒性的重要组成部分 [40] 。研究显示,Aβ可在细胞水平诱导炎性细胞因子TNF-α和IL-6的表达水平显著升高 [41] ,在AD发病早期,炎性细胞因子基因相关转录因子NF-κB可被Aβ沉积激活 [42] ,炎性细胞因子在AD的各个阶段都呈高水平表达,提示神经炎症与AD病理有着紧密的相关性 [43] ,也有研究证明TNF-α和IFN-γ能促进Aβ生成 [44] ,因此炎症反应与AD病理紧密相关。哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)是一类丝氨酸/苏氨酸激酶(serine/threonine kinase),属磷脂酰肌醇相关激酶家族 [45] ,广泛参与细胞生长、增殖、脂质合成等细胞活动的调控 [46] 。越来越多研究表明,mTOR与AD病理密切相关 [47] ;诸多研究表明,AD脑组织存在mTOR过表达和过度激活的现象,如Siman R等在AD动物模型中观察到,Aβ累积可上调mTOR的表达水平 [48] ;Liu Y C等在老鼠海马区注射Aβ,观察到海马组织TNF-α表达水平显著上调、mTOR表达水平显著上调和激活的现象 [49] 。研究表明,mTOR具有调控炎性细胞因子如IL-1β,TNF-α及IFN-γ的作用 [50] ,如Dhingra R等的研究显示,mTOR能激活NF-Κb [51] ,而Mengke N S等的研究显示,mTOR抑制剂雷帕霉素可下调脂多糖诱导的IL-1β和IL-6的mRNA表达水平 [52] ,提示脂多糖可能通过激活mTOR促进炎性细胞因子表达,炎性细胞因子IL-1β和IL-6的释放可破坏正常的神经生理功能 [53] 。因此,mTOR被认为是AD治疗的重要靶点(如图1)。

注释:1) BACE1的过表达促进Aβ的生成和沉积,过量的Aβ通过某种机制促进氧化应激,对神经元造成氧化损伤;2) Aβ沉积导致mTOR过度激活,继而促进神经炎症及tau蛋白过磷酸化形成NFT,最终引起神经元变性死亡。

Figure 1. Overview of the pathogenesis of AD

图1. AD发病机理推理概述

4. Aβ与神经原纤维缠结、自噬

Tau蛋白是一类微管相关蛋白,主要表达于神经元轴突,对微管组装和维持微管稳定具有重要作用 [54] ,AD的主要病理标志之一NFT,则由Tau过度磷酸化与微管脱离形成,研究发现,异常过磷酸化的Tau蛋白,无论在溶解状态还是凝聚状态,都不能与微管蛋白相互作用 [55] ,NFT的形成导致神经元细胞形态异常、轴突运输功能丢失及突触功能丢失等神经退性病变 [56] 。大量研究显示,mTOR过度激活与AD发病紧密相关 [57] ,mTOR信号通路的激活可促进Tau蛋白病变,而抑制mTOR信号通路则可缓解Tau蛋白病变 [58] ;有研究证明,Tau蛋白可被mTOR直接磷酸化,且Tau蛋白的聚集、表达都受mTOR影响 [59] ,而体内外研究表明,mTOR抑制剂雷帕霉素可降低Tau蛋白水平 [60] ,且能改善AD模型鼠的认知功能缺陷并能降低Aβ水平 [61] ;另有研究表明,mTOR的过度激活可抑制自噬作用(autophagy),从而降低自噬作用对Aβ的清除、加剧Aβ的沉积 [62] ;诸多研究显示,自噬功能损伤与AD发病密切相关 [63] 。神经元由于高度分化失去分裂能力,因而不能通过细胞分裂稀释不断积累的毒性物质,只能通过自噬作用清除胞内毒性物质或是受损的细胞器以维持细胞内稳态。mTOR的异常过度激活与自噬作用、Tau蛋白过磷酸化密切相关,提示mTOR可作为AD治疗的重要靶点(如图1)。

5. AD药物现状与展望

目前,运用最广泛的AD药物包括胆碱酯酶抑制剂(Acetylcholinesterase inhibitors, AChEI):盐酸多奈哌齐(Donepezil)、加兰他敏(Galantamine Reminyl)、利凡斯的明(Rivastigmine)及兴奋性氨基酸受体拮抗剂美金刚(Memantine) [64] ;然而,AChEI类药物往往导致Tau蛋白磷酸化水平升高 [65] ,而且AChEI与美金刚存在不同程度的毒副作用。越来越多的证据显示,Aβ沉积是起始AD的关键因素,因此大多AD治疗策略研究都聚焦在如何抑制或清除Aβ。然而,2014年,瑞士罗氏公司(Roche)发布公告称其在研的AD新药Crenezumab在二期临床实验中失败;2016年,美国礼来公司(Eli Lilly and Company)也宣布其研发的新药Solanezumab (一类靶向作用可溶性Aβ单体的疫苗)在三期临床试验中失败,这表明仅仅作用Aβ单个靶点难以到达理想的抗AD疗效。大量研究显示,Aβ沉积导致氧化应激、炎症反应、神经原纤维缠结及神经元凋亡,最终导致认知功能障碍、行为异常等临床症状,现有的AD药物相关研究,也大多基于抗氧化、抗炎症的观点,且抗炎症、抗氧化类药物能在细胞水平及动物水平上取得理想的抗AD效果,表明氧化应激、神经炎症确与AD病理密切相关。越来越多的证据显示,AD是一类多因素疾病,多靶点治疗无疑是当下和将来AD药物研发的新策略。

6. 结语

脑组织神经元外Aβ异常沉积被广泛认为是起始神经元突触丢失,并最终导致神经元死亡的关键因素 [66] [67] 。尽管存在多种Aβ诱导的神经毒性机制假说,但大量研究证明,Aβ诱导的氧化应激是AD病理的重要促进因素,Aβ引起神经元ROS水平上升,对脂质、DNA以及RNA等生物大分子造成氧化损伤,最终导致神经元的变性死亡 [7] [8] 。线粒体是细胞的产能中心,机体吸收的氧气大部分作为电子传电链终端电子受体参与ATP的生成,是产生ROS的主要细胞器。在正常生理情况下,约有2%的O2被电子传递链底物端漏出的电子还原生成ROS [68] 。低水平的ROS,可作为细胞内氧化还原信使,并行使传递、调控细胞内信号的功能 [69] ,而过量的ROS则对细胞造成过氧化损伤,最终导致细胞凋亡 [70] 。因此Aβ诱导的氧化应激是AD病理的重要促进因素。

mTOR的过度激活与过表达与Tau蛋白的过磷酸化紧密相关,Tau蛋白的过磷酸化导致NFT、微管结构不稳定、细胞形态异常及轴突运输功能紊乱,最终导致神经元死亡 [56] 。同时,mTOR的过度激活与过表达与神经炎症紧密相关,mTOR的过度激活促进炎性细胞因子的表达。此外,mTOR的过度激活可抑制自噬作用,从而减弱自噬作用对Aβ等毒性物质的清除,被认为是Aβ沉积的重要原因。尽管AD的确切病理机制仍有待探索阐明,但越来越多的证据表明,Aβ过度沉积、mTOR过度激活与过表达与AD病理密切相关;Aβ累积可通过诱导氧化应激、Tau蛋白过磷酸化、线粒体功能损伤导致神经退行性病变 [71] [72] 。研究显示,AD患者脑组织存在BACE1过表达的现象 [73] ,BACE1的过表达促进APP转变成Aβ,过量的Aβ可能通过某种机制促进ROS的过度生成,加剧氧化应激;此外,Aβ可能通过某种机制过度激活mTOR,继而促进神经炎症、Tau蛋白过磷酸化形成NFT,最终引起神经元变性死亡,综上,Aβ介导的氧化应激、神经炎症、微管结构异常均是AD病理的重要促进因素,Aβ、BACE1、mTOR及Tau蛋白可作为AD药物研发的重要靶点。

文章引用:
王天佐, 张莹, 薛真真, 朱启顺. 阿尔兹海默病发病机理概述及治疗策略展望[J]. 临床医学进展, 2018, 8(1): 85-92. https://doi.org/10.12677/ACM.2018.81016

参考文献

[1] Koo, E.H., Lansbury, P.T. and Kelly, J.W. (1999) Amyloid Diseases: Abnormal Protein Aggregation in Neurodegeneration. Pro-ceedings of the National Academy of Sciences of the United States of America, 96, 9989.
https://doi.org/10.1073/pnas.96.18.9989
[2] Organization, W.H. (2012) Dementia: A Public Health Priority. Perspect Public Health, 5, 123-125.
[3] Hardy, J. (2000) Pathways to Primary Neurodegenerative Disease. Neurologia, 924, 29-34.
https://doi.org/10.1111/j.1749-6632.2000.tb05556.x
[4] Evans, D.A., Funkenstein, H.H., Albert, M.S., et al. (1989) Prevalence of Alzheimer’s Disease in a Community Population of Older Persons. Higher than Previously Reported. JAMA, 262, 2551-2556.
https://doi.org/10.1001/jama.1989.03430180093036
[5] Selkoe, D.J. (2002) Alzheimer’s Disease Is a Synaptic Failure. Science, 298, 789.
https://doi.org/10.1126/science.1074069
[6] Walsh, D.M. and Selkoe, D.J. (2004) Deciphering the Molecular Basis of Memory Failure in Alzheimer’s Disease. Neuron, 44, 181-193.
https://doi.org/10.1016/j.neuron.2004.09.010
[7] Butterfield, D.A., Reed, T., Newman, S.F., et al. (2007) Roles of Amyloid β-Peptide-Associated Oxidative Stress and Brain Protein Modifications in the Pathogenesis of Alzheimer's Disease and Mild Cognitive Impairment. Free Radical Biology & Medicine, 43, 658-677.
https://doi.org/10.1016/j.freeradbiomed.2007.05.037
[8] Woo, H.N., Park, J.S., Gwon, A.R., et al. (2009) Alzheimer's Disease and Notch Signaling. Biochemical & Biophysical Research Communications, 390, 1093-1097.
https://doi.org/10.1016/j.bbrc.2009.10.093
[9] Huang, X., Moir, R.D., Tanzi, R.E., et al. (2004) Redox-Active Metals, Oxida-tive Stress, and Alzheimer’s Disease Pathology. Annals of the New York Academy of Sciences, 1012, 153.
https://doi.org/10.1196/annals.1306.012
[10] Clark, T.A., Pil, L.H., Rolston, R.K., et al. (2010) Oxidative Stress and its Impli-cations for Future Treatments and Management of Alzheimer Disease. International Journal of Biomedical Science Ijbs, 6, 225.
[11] Guan, Z. (2008) Cross-Talk between Oxidative Stress and Modifications of Cholinergic and Glutaminergic Receptors in the Pathogenesis of Alzheimer’s Disease. Acta Pharmacologica Sinica, 29, 773-780.
[12] 吕志迈, 徐运. 淀粉样蛋白代谢相关基因与阿尔茨海默病的研究进展[J]. 国际神经病学神经外科学杂志, 2007, 34(6): 527-530.
[13] 黄叶静, 刘协和, 邓红, 王英成, 李胜富. 淀粉样多肽诱导神经元凋亡和氧化应激机制的实验观察[J]. 中华神经科杂志, 2002, 10(4): 250-251.
[14] Lustbader, J.W., Cirilli, M., Lin, C., Xu, H.W., Takuma, K., Wang, N., Caspersen, C., Chen, X., Pollak, S. and Chaney, M. (2004) ABAD Directly Links Aβ to Mitochondrial Toxicity in Alzheimer’s Disease. Science, 304, 448-452.
https://doi.org/10.1126/science.1091230
[15] Youn, K., Lee, S., Jeong, W.S., Ho, C.T. and Jun, M. (2016) Protective Role of Corilagin on Aβ25-35-Induced Neurotoxicity: Suppression of NF-κB Signaling Pathway. Journal of Medicinal Food, 19, 901-911.
https://doi.org/10.1089/jmf.2016.3714
[16] Chen, Z. and Zhong, C. (2014) Oxidative Stress in Alzheimer’s Disease. Neuros-cience Bulletin, 18, 271-281.
[17] Sultana, R., Mecocci, P., Mangialasche, F., Cecchetti, R., Baglioni, M. and Butterfield, D.A. (2011) Increased Protein and Lipid Oxidative Damage in Mitochondria Isolated from Lymphocytes from Patients with Alzheimer’s Disease: Insights into the Role of Oxidative Stress in Alzheimer’s Disease and Initial Investigations into a Potential Biomarker for This. Journal of Alzheimer’s Disease, 24, 77-84.
[18] Che, H., Du, L., Cong, P., Tao, S., Ding, N., Wu, F., Xue, C., Xu, J. and Wang, Y. (2017) Cerebrosides from Sea Cucumber Protect against Oxidative Stress in SAMP8 Mice and PC12 Cells. Journal of Medicinal Food, 20, 392-402.
https://doi.org/10.1089/jmf.2016.3789
[19] Fadi, M. and Serge, G. (2010) Update on the Pharmacological Treatment of Alz-heimer’s Disease. Current Neuropharmacology, 8, 69-80.
https://doi.org/10.2174/157015910790909520
[20] Soodi, M., Saeidnia, S., Sharifzadeh, M., et al. (2016) Satureja Bachtiarica Ameliorate Beta-Amyloid Induced Memory Impairment, Oxidative Stress and Cholinergic Deficit in Animal Model of Alzheimer’s Disease. Metabolic Brain Disease, 31, 395-404.
https://doi.org/10.1007/s11011-015-9773-y
[21] Hayeon, J., Jooyoun, K., Hongkyu, L., et al. (2010) Leaf and Stem of Vitis Amurensis and Its Active Components Protect against Amyloid β Protein (25-35)-Induced Neurotoxicity. Archives of Pharmacal Research, 33, 1655-1664.
https://doi.org/10.1007/s12272-010-1015-6
[22] Guo, X., Sun, G., Zhou, T., et al. (2017) LX2343 Alleviates Cognitive Im-pairments in AD Model Rats by Inhibiting Oxidative Stress-Induced Neuronal Apoptosis and Tauopathy. Acta Pharmacologica Sinica, 38, 1104-1119.
https://doi.org/10.1038/aps.2016.128
[23] Garciaalloza, M., Borrelli, L.A., Hyman, B.T., et al. (2010) Antioxidants Have a Rapid and Long-Lasting Effect on Neuritic Abnormalities in APP:PS1 Mice. Neurobiology of Aging, 31, 2058-2068.
https://doi.org/10.1016/j.neurobiolaging.2008.11.006
[24] Liang, W., Zhao, X., Feng, J., et al. (2016) Ursolic Acid Attenuates Beta-Amyloid-Induced Memory Impairment in Mice. Arquivos de Neuro-Psiquiatria, 74, 482-488.
https://doi.org/10.1590/0004-282x20160065
[25] Peters, I., Igbavboa, U., Schütt, T., et al. (2009) The Interaction of Be-ta-Amyloid Protein with Cellular Membranes Stimulates Its Own Production. Biochimica et Biophysica Acta (BBA)—Biomembranes, 1788, 964-972.
https://doi.org/10.1016/j.bbamem.2009.01.012
[26] Drake, J. (2001) Evidence of Oxidative Damage in Alzheimer’s Disease Brain: Central Role for Amyloid Beta-Peptide. Trends in Molecular Medicine, 7, 548-554.
https://doi.org/10.1016/S1471-4914(01)02173-6
[27] Butterfield, D.A., Castegna, A., Lauderback, C.M., et al. (2015) Evidence That Amyloid Beta-Peptide-Induced Lipid Peroxidation and Its Sequelae in Alzheimer’s Disease Brain Contribute to Neuronal Death. Neurobiology of Aging, 23, 655-664.
https://doi.org/10.1016/S0197-4580(01)00340-2
[28] Yang, P., He, X.Q., Peng, L., et al. (2007) The Role of Oxidative Stress in Hormesis Induced by Sodium Arsenite in Human Embryo Lung Fibroblast (HELF) Cellular Proliferation Model. Journal of Toxicology & Environmental Health Part A, 70, 976-983.
https://doi.org/10.1080/15287390701290832
[29] Gandhi, S. and Abramov, A.Y. (2012) Mechanism of Oxidative Stress in Neurodegeneration. Oxidative Medicine and Cellular Longevity, 2012, Article ID: 428010.
https://doi.org/10.1155/2012/428010
[30] Finkel, T. (1999) Signal Transduction by Reactive Oxygen Species. Journal of Cell Biology, 65, 337-340.
[31] Takuma, K., Yao, J., Huang, J., et al. (2005) ABAD Enhances Aszlig Beta-Induced Cell Stress via Mi-tochondrial Dysfunction. FASEB Journal, 19, 597-598.
https://doi.org/10.1096/fj.04-2582fje
[32] Ochoa, J.J., Pamplona, R., Ramirez-Tortosa, M.C., et al. (2011) Age-Related Changes in Brain Mitochondrial DNA Deletion and Oxidative Stress Are Diffe-rentially Modulated by Dietary Fat Type and Coenzyme Q₁₀. Free Radical Biology & Medicine, 50, 1053-1064.
[33] Innis, S.M. (2005) Essential Fatty Acid Transfer and Fetal Development. Placenta, 26, S70-S75.
[34] Varadarajan, S., Yatin, S., Aksenova, M., et al. (2000) Review: Alzheimer’s Amyloid β-Peptide-Associated Free Radical Oxidative Stress and Neurotoxicity. Journal of Structural Biology, 130, 184-208.
https://doi.org/10.1006/jsbi.2000.4274
[35] Mattson, M.P. (2004) Pathways towards and away from Alzheimer’s Disease. Na-ture, 430, 631-639.
https://doi.org/10.1038/nature02621
[36] Ellis, C.R., Tsai, C.C., Lin, F.Y. and Shen, J. (2017) Conformational Dynamics of Cathepsin D and Binding to a Small-Molecule BACE1 Inhibitor. Journal of Computational Chemistry, 38, 1260-1269.
https://doi.org/10.1002/jcc.24719
[37] Yan, R. and Vassar, R. (2014) Targeting the β Secretase BACE1 for Alzheimer’s Disease Therapy. The Lancet Neurology, 13, 319-329.
https://doi.org/10.1016/S1474-4422(13)70276-X
[38] Eikelenboom, P., Zhan, S.S., van Gool, W.A., et al. (1996) Inflammatory Mechanisms in Alzheimer’s Disease. Trends in Pharmacological Sciences, 246, 124-128.
[39] Mcgeer, P.L. and Mcgeer, E.G. (1995) The Inflammatory Response System of Brain: Implications for Therapy of Alz-heimer and Other Neurodegenerative Diseases. Brain Research Brain Research Reviews, 21, 195-218.
https://doi.org/10.1016/0165-0173(95)00011-9
[40] Esposito, G., De, F.D., Maiuri, M.C., et al. (2006) Cannabidiol Inhibits Inducible Nitric Oxide Synthase Protein Expression and Nitric Oxide Production in Beta-Amyloid Stimulated PC12 Neurons through p38 MAP Kinase and NF-kappaB Involvement. Neuroscience Letters, 399, 91-95.
https://doi.org/10.1016/j.neulet.2006.01.047
[41] Andressa, B., Frozza, R.L., André, M., et al. (2012) Indomethacin-Loaded Lipid-Core Nanocapsules Reduce the Damage Triggered by Aβ1-42 in Alzheimer’s Disease Models. International Journal of Nano-medicine, 7, 4927-4942.
[42] Kaltschmidt, B., Uherek, M., Volk, B., et al. (1997) Transcription Factor NF-Kappa B Is Activated in Primary Neurons by Amyloid Beta Peptides and in Neurons Surrounding Early Plaques from Patients with Alzheimer Disease. Pro-ceedings of the National Academy of Sciences of the United States of America, 94, 2642-2647.
https://doi.org/10.1073/pnas.94.6.2642
[43] Sastre, M., Klockgether, T. and Heneka, M.T. (2006) Contribution of Inflammatory Processes to Alzheimer’s Disease: Molecular Mechanisms. International Journal of Developmental Neuroscience the Official Journal of the International Society for Developmental Neuroscience, 24, 167-176.
https://doi.org/10.1016/j.ijdevneu.2005.11.014
[44] Liu, H., Wang, J., Wang, J., et al. (2015) Paeoniflorin Attenuates Aβ1-42-Induced Inflammation and Chemotaxis of Microglia in Vitro and Inhibits NF-κB- and VEGF/Flt-1 Signaling Pathways. Brain Research, 1618, 149-158.
https://doi.org/10.1016/j.brainres.2015.05.035
[45] Baker, H., Sidorowicz, A., Sehgal, S.N., et al. (1978) Rapamycin (AY-22,989), a New Antifungal Antibiotic. III. In Vitro and in Vivo Evaluation. Journal of Antibiotics, 31, 539-545.
https://doi.org/10.7164/antibiotics.31.539
[46] Huang, K. and Fingar, D.C. (2014) Growing Knowledge of the mTOR Signaling Network. Seminars in Cell & Developmental Biology, 36, 79-90.
https://doi.org/10.1016/j.semcdb.2014.09.011
[47] Richardson, A., Galvan, V., Lin, A.L., et al. (2015) How Longevity Research Can Lead to Therapies for Alzheimer’s Disease: The Rapamycin Story. Experimental Gerontology, 68, 51-58.
https://doi.org/10.1016/j.exger.2014.12.002
[48] Siman, R., Cocca, R. and Dong, Y. (2015) The mTOR Inhibitor Rapamycin Mitigates Perforant Pathway Neurodegeneration and Synapse Loss in a Mouse Model of Early-Stage Alzheimer-Type Tauopathy. PLoS ONE, 10, e0142340.
https://doi.org/10.1371/journal.pone.0142340
[49] Liu, Y.C., Gao, X.X., Ling, C., et al. (2017) Rapamycin Suppresses Aβ25-35- or LPS-Induced Neuronal Inflammation via Modulation of NF-κB Signaling. Neuroscience, 355, 188-199.
https://doi.org/10.1016/j.neuroscience.2017.05.005
[50] Huang, H., Chang, H., Tsai, M., et al. (2016) 6-Mercaptopurine Atte-nuates Tumor Necrosis Factor-α Production in Microglia through Nur77-Mediated Transrepression and PI3K/Akt/mTOR Signal-ing-Mediated Translational Regulation. Journal of Neuroinflammation, 13, 78.
https://doi.org/10.1186/s12974-016-0543-5
[51] Dhingra, R., Gang, H., Wang, Y., et al. (2013) Bidirectional Regulation of Nuclear Factor-κB and Mammalian Target of Rapamycin Signaling Functionally Links Bnip3 Gene Repression and Cell Survival of Ventricular Myocytes. Circulation Heart Failure, 6, 335-343.
https://doi.org/10.1161/CIRCHEARTFAILURE.112.000061
[52] Mengke, N.S., Hu, B., Han, Q.P., et al. (2016) Rapamycin Inhibits Lipopolysaccharide-Induced Neuroinflammation in Vitro and in Vivo. Molecular Medicine Reports, 14, 4957-4966.
https://doi.org/10.3892/mmr.2016.5883
[53] Varnum, M.M. and Ikezu, T. (2012) The Classification of Microglial Activation Phenotypes on Neurodegeneration and Regeneration in Alzheimer’s Disease Brain. Archivum Immunologiae Et Therapiae Experi-mentalis, 60, 251-266.
https://doi.org/10.1007/s00005-012-0181-2
[54] Weingarten, M.D., Lockwood, A.H., Hwo, S.Y., et al. (1975) A Protein Factor Essential for Microtubule Assembly. Proceedings of the National Academy of Sciences of the United States of America, 72, 1858-1862.
https://doi.org/10.1073/pnas.72.5.1858
[55] Iqbal, K., Liu, F., Gong, C.X., et al. (2010) Tau in Alzheimer Disease and Related Tauopathies. Current Alzheimer Research, 7, 656-664.
https://doi.org/10.2174/156720510793611592
[56] Roy, S., Zhang, B., Lee, V.M.Y., et al. (2005) Axonal Transport Defects: A Common Theme in Neurodegenerative Diseases. Acta Neuropathologica, 109, 5-13.
https://doi.org/10.1007/s00401-004-0952-x
[57] Cai, Z., Chen, G., He, W., et al. (2015) Activation of mTOR: A Culprit of Alzheimer’s Disease? Neuropsychiatric Disease & Treatment, 11, 1015-1130.
[58] Caccamo, A., Magrì, A., Medina, D.X., et al. (2013) mTOR Regulates Tau Phosphorylation and Degradation: Implications for Alzheimer’s Disease and Other Tauopathies. Aging Cell, 12, 370-380.
https://doi.org/10.1111/acel.12057
[59] Tang, Z., Bereczki, E., Zhang, H., et al. (2013) Mammalian Target of Rapamycin (mTor) Mediates Tau Protein Dyshomeostasis. Journal of Biological Chemistry, 288, 15556-15570.
https://doi.org/10.1074/jbc.M112.435123
[60] Caccamo, A., Majumder, S., Richardson, A., et al. (2010) Molecular Interplay between Mammalian Target of Rapamycin (mTOR), Amyloid-β, and Tau: Effects on Cognitive Impairments. Journal of Biological Chemistry, 285, 13107-13120.
https://doi.org/10.1074/jbc.M110.100420
[61] Spilman, P., Podlutskaya, N., Hart, M.J., et al. (2010) Inhibition of mTOR by Rapamycin Abolishes Cognitive Deficits and Reduces Amyloid-β Levels in a Mouse Model of Alzheimer’s Disease, PLoS ONE, 5, e9979.
[62] Li, L., Zhang, S., Zhang, X., et al. (2013) Autophagy Enhancer Carbamazepine Alleviates Memory Deficits and Cerebral Amyloid-β Pathology in a Mouse Model of Alzheimer’s Disease. Current Alzheimer Research, 10, 433-441.
https://doi.org/10.2174/1567205011310040008
[63] Qian, L., Yi, L. and Miao, S. (2017) Autophagy and Alzheimer’s Disease. Cellular & Molecular Neurobiology, 37, 1-12.
[64] Bachurin, S.O., Bovina, E.V. and Ustyugov, A.A. (2017) Drugs in Clinical Trials for Alzheimer’s Disease: The Major Trends. Medicinal Research Reviews, 37, 1186-1225.
https://doi.org/10.1002/med.21434
[65] Chalmers, K.A., Wilcock, G.K., Vinters, H.V., et al. (2009) Cholinesterase Inhibitors May Increase Phosphorylated Tau in Alzheimer’s Disease. Journal of Neurology, 256, 717-720.
https://doi.org/10.1007/s00415-009-5000-2
[66] Carter, J. and Lippa, C.F. (2001) Beta-Amyloid, Neuronal Death and Alzhei-mer’s Disease. Current Molecular Medicine, 1, 733-737.
https://doi.org/10.2174/1566524013363177
[67] Hardy, J. and Selkoe, D.J. (2002) The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics. Science, 297, 353-356.
https://doi.org/10.1126/science.1072994
[68] Chance, B., Sies, H. and Boveris, A. (1979) Hydroperoxide Metabolism in Mammalian Organs. Physiological Reviews, 59, 527-605.
https://doi.org/10.1152/physrev.1979.59.3.527
[69] 魏燕, 辛晓燕. 活性氧调控的细胞凋亡信号[J]. 现代肿瘤医学, 2011, 19(2): 371-373.
[70] Circu, M.L. and Aw, T.Y. (2010) Reactive Oxygen Species, Cellular Redox Systems, and Apoptosis. Free Radical Biology & Medicine, 48, 749-762.
https://doi.org/10.1016/j.freeradbiomed.2009.12.022
[71] Busciglio, J., Lorenzo, A., Yeh, J., et al. (1995) β-Amyloid Fibrils Induce Tau Phosphorylation and Loss of Microtubule Binding. Neuron, 14, 879-888.
https://doi.org/10.1016/0896-6273(95)90232-5
[72] Khan, A., Vaibhav, K., Javed, H., Khan, M.M., Tabassum, R., Ahmed, M.E., Srivastava, P., Khuwaja, G., Islam, F., Siddiqui, M.S., et al. (2012) Attenuation of Abeta-Induced Neurotoxicity by Thymo-quinone via Inhibition of Mitochondrial Dysfunction and Oxidative Stress. Molecular and Cellular Biochemistry, 369, 55-65.
https://doi.org/10.1007/s11010-012-1368-x
[73] Chen, Y., Huang, X., Zhang, Y., et al. (2012) Alzheimer’s Beta-Secretase (BACE1) Regulates the cAMP/PKA/CREB Pathway Independently of Beta-Amyloid. Journal of Neuroscience, 32, 11390-11395.