药学学报  2019, Vol. 54 Issue (6): 984-990     DOI: 10.16438/j.0513-4870.2018-1107   PDF    
药物调节自噬治疗阿尔茨海默病
谭成勇1, 田慧珍1, 况煌1, 洪芬芳2, 杨树龙1     
1. 南昌大学基础医学院, 江西 南昌 330031;
2. 南昌大学基础医学实验教学中心, 江西 南昌 330006
摘要: 阿尔茨海默病(Alzheimer's disease,AD)是以认知功能障碍为临床表现的疾病。过去虽然对AD发病机制研究取得了显著进展,但阻断AD病情发展的有效治疗方法并不令人满意。自噬(autophagy)异常被认为参与AD发病机制,自噬的调节可能成为AD治疗新策略。经mTOR依赖性和非依赖性(Bcl-2/Beclin-1、GSK-3β和p-AKT等)途径调节自噬的药物显示出很好的缓解AD症状作用。此外,一些从植物中提取出的化合物也被报道可经多途径、多靶标调节自噬阻止AD进展。本文对近期有关药物包括植物提取药物调节自噬治疗AD的研究进展作一综述,为临床治疗AD提供新的理论基础。
关键词: 自噬     阿尔茨海默病     植物提取化合物     药物    
Medications regulate autophagy for treatment of Alzheimer's disease
TAN Cheng-yong1, TIAN Hui-zhen1, KUANG Huang1, HONG Fen-fang2, YANG Shu-long1     
1. College of Basic Medicine, Nanchang University, Nanchang 330031, China;
2. Medical Experimental Teaching Center, Nanchang University, Nanchang 330006, China
Abstract: Alzheimer's disease (AD) is characterized clinically as irreversible cognitive dysfunction. Although a significant progress has been made in the study of AD pathogenesis, the effective measures to block AD progress have not been satisfactory. Abnormal autophagy is thought to be involved in the pathogenesis of AD, and regulation of autophagy may become a new strategy for AD treatment. Some medicines, which regulate autophagy by mTOR-dependent and independent (Bcl-2/Beclin-1, GSK-3β, and p-AKT) pathways, have shown excellent effects in alleviating AD symptoms. In addition, certain compounds extracted from plants have also been reported to regulate autophagy and prevent AD progression through multiple pathways and multiple targets. This article reviews the recent advances in the regulation of autophagy and AD treatment. It provides a new theoretical basis for clinical treatment of AD.
Key words: autophagy     Alzheimer's disease     plant extract compound     medicine    

阿尔茨海默病(Alzheimer's disease, AD)是一种与年龄相关的神经退行性疾病, 病理特征为β样淀粉蛋白(β-amyloid, Aβ)沉积导致老年斑(senile plaque)形成和Tau蛋白过度磷酸化导致神经原纤维缠结(neurofibrillary tangles)形成[1]。自噬是真核细胞内的一种分解代谢过程, 可去除功能受损的细胞、细胞器以及功能失调的蛋白质聚集体[2], 自噬过程包括自噬诱导、囊泡成核和扩张和自噬体形成[3]。自噬在AD发病过程中起着重要作用, 自噬涉及的信号转导途径复杂多样(图 1), 该发现推动了一系列关于药物调节自噬的研究。针对调节自噬信号途径的包括一些天然化合物在内的药物在AD动物模型实验中表现出巨大治疗潜能。本文主要对上述相关最新研究进展作一综述。

Figure 1 Major autophagy pathway. AMPK: Adenosine 5'-monophosphate (AMP)-activated protein kinase; ULK1: Unc-51-like kinase 1; SIRT1: Silent mating type information regulation 2 homolog-1; Bcl-2: B-cell lymphoma-2; TFEB: Transcriptional factor EB
1 非植物提取药物 1.1 经mTOR依赖性途径影响自噬的药物

哺乳动物雷帕霉素靶标(mammalian target of rapamycin, mTOR)是一种重要的丝氨酸-苏氨酸蛋白酶, 由mTORC1和mTORC2两种复合物组成。mTOR是自噬过程主要的调控者, 其活性受饥饿、生长因子等因素调节, mTOR依赖性途径激活抑制自噬起始过程[4]。目前在AD患者中发现mTOR途径被激活, 而mTOR途径抑制对改善AD症状有一定作用[5]

1.1.1 经典mTOR抑制剂—雷帕霉素

雷帕霉素(rapamycin)是一种自噬特异性诱导剂, 经抑制mTOR依赖性途径, 从而上调自噬标记因子如ULK1、p62、Beclin-1、LC3-I/LC3-II、Atg3/5/7/12等诱导自噬。Singh等[6]证实Aβ1-42降低Ⅲ类磷脂酰肌醇3-激酶PI3K、蛋白激酶AKT 1和环磷腺苷效应元件结合蛋白(cAMP-response element binding protein, CREB)磷酸化水平, 雷帕霉素可诱导自噬缓解此作用, 改变Aβ1-42神经变性结果, 提示雷帕霉素经PI3K/AKT1/mTOR/CREB途径激活自噬并改善AD病变。研究显示, 雷帕霉素酯类似物CCI-779 (rapamycin ester analog CCI-779/temsirolimus, CCI-779)在Tau突变转基因AD鼠模型(Tg鼠)中可减少Tau聚集体形成, 显著降低野生型鼠和Tg30鼠mTOR信号转导。但进一步实验表明, CCI-779治疗并未完全阻止早期或晚期Tg30鼠Tau病变进展, 提示mTOR依赖性自噬刺激在阻止Tau聚集方面可能并不完全有效[7], 并且有报道表明, 雷帕霉素也是一种免疫抑制剂, 长期使用雷帕霉素可能使AD患者免疫系统受到损伤, 其潜在的不利影响需进一步证实[8]

1.1.2 经p-AKT-mTOR途径影响自噬的药物

除雷帕霉素这个经典mTOR抑制剂, 其他药物也表现出对mTOR相关途径的抑制效应(表 1)[6-13]。AKT是mTOR上游的正性调节分子, 可直接启动mTOR磷酸化, 从而激活mTOR途径抑制自噬。早期研究显示, AKT通过PI3K激活后产生磷脂酰肌醇3, 4, 5-三磷酸(PIP3), 并通过T389处的下游激酶mTOR p70S6K的磷酸化介导多种细胞内功能, 而另一项研究表明, 触发mTORC2负反馈环可激活AKT[14-16], 随后实验发现, 孕酮激素(progesterone)可在经Aβ处理的星形胶质细胞中提高p-AKT水平, 下调mTOR信号转导, 因此学者猜测孕酮激素通过刺激mTORC2负反馈环上调p-AKT。但触发mTORC2负反馈环如何升高mTOR正性调节分子p-AKT而且同时降低p-mTOR, 需进一步研究。此外, 孕酮激素还显著抑制促炎细胞因子白细胞介素-1 (interleukin-1β, IL-1β)和肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α)水平, 提示孕酮激素可抑制Aβ处理的星形胶质细胞中p-mTOR水平, 激活自噬, 产生神经保护作用[9]

Table 1 The effects of non-plant extracts on autophagy and Alzheimer's disease (AD). +: Activation; -: Inhibition; ↑: Enhancement; ↓: Decrease
1.1.3 经AMPK-mTOR途径影响自噬的药物

近来研究表明, AMPK-mTOR途径参与调节自噬起始阶段, AMP依赖的蛋白激酶[adenosine 5'-monophosphate (AMP)-activated protein kinase, AMPK]活化可抑制mTOR表达, 从而促进自噬的激活。然而, 在AD发病过程中可观测到AMPK减少, 自噬发生异常。Zhang等[10, 11]经蛋白质免疫印迹(Western blot)实验发现硒蛋氨酸(selenomethionine)处理大鼠海马和皮质后, 自噬标记因子LC3-II表达显著增加、p-AMPK水平升高、mTOR表达抑制、p70S6K水平显著减少, 提示硒蛋氨酸可能经AMPK-mTOR介导的自噬途径促进Tau蛋白降解, 改善AD症状。随后还发现硒蛋氨酸也可经调节AKT-mTOR-p70S6K途径增加自噬体-溶酶体融合以及自噬降解来促进Aβ清除。上述研究显示, 硒蛋氨酸经多种途径调节自噬促进Tau和Aβ降解清除, 提示硒蛋氨酸治疗AD有巨大潜能。斯达汀处理星形胶质细胞可减少mTOR磷酸化, 提高LC3-II表达水平。他汀类药物可经一种基于自噬的非常规分泌途径诱导星形胶质细胞分泌胞外胰岛素降解酶(IDE), 而IDE下调细胞外Aβ水平, 进一步研究发现使用AMPK抑制剂处理细胞可逆转上述效果, 提示斯达汀经AMPK-mTOR途径激活星形胶质细胞自噬, 可为治疗AD提供一个潜在的新型治疗靶点[12]。西洛他唑(cilostazol)可显著降低N2a细胞内Aβ聚集和磷酸化Tau含量, 改善AD鼠模型空间学习和记忆能力, 并且显著增加p-ACC (AMPK激活的最初靶标)和p-AMPKα的表达。而AD鼠模型经去乙酰化酶(sirtuin 1, SIRT1)基因敲除处理后, p-LKB1和p-AMPKα表达量显著下降, 西洛他唑处理未能增加p-LKB1和p-AMPKα表达, 提示西洛他唑与AMPK和SIRT1的紧密联系, 其通过激活SIRT1偶联p-LKB1/p-AMPKα并抑制mTOR活化, 增强自噬减少Aβ积累[13]

1.2 mTOR非依赖性促进自噬的药物

尽管mTOR依赖性途径是治疗AD热门靶点, 然而经药物抑制mTOR途径增强自噬可带来很多不良反应, 因此经其他途径激活自噬是一个新选择。以下罗列了最近研究证实的一些可经不同mTOR非依赖性途径调节自噬对治疗AD有前景的药物。① Bcl-2/Beclin-1途径。Xue等[17]发现Beclin-1表达水平与细胞活力呈正相关, 在损伤发生前激活Beclin-1依赖性自噬可阻止神经细胞死亡, 而抑制Beclin-1依赖性自噬则加速细胞死亡, 提示促进Beclin-1依赖性自噬在AD中可能具有潜在预防作用。② GSK-3β途径。实验表明糖原合成酶激酶-3β (GSK-3β)能激活自噬, 低浓度锂(lithium)可抑制GSK-3β减轻自噬[18]。然而, 在锂的体外实验中发现, 高浓度锂可增强自噬, 因此锂是否低浓度减轻自噬、高浓度增强自噬尚不明确, 但长期锂治疗可能会减轻脑脊液中AD病变, 表现为脑脊液中磷酸化Tau水平降低, 提示锂增强自噬可能有助于改善AD病情[19]。③自噬-溶酶体途径。GTM-1是一种新型mTOR非依赖性途径自噬诱导剂, Chu等[20]发现GMT-1在人神经元中可经AKT非依赖性和mTOR非依赖性方式促进自噬清除Aβ, 且可逆转自噬-溶酶体融合抑制剂胡萝卜素和天冬酰胺导致的自噬通量降低, 缓解AD鼠模型Aβ病变和改善其认知缺陷。

2 植物提取化合物类

研究显示, 在植物提取物中存在调节自噬的化合物, 许多具有优良药理作用的天然产物是控制或预防AD有效选择, 下文总结基于调节自噬治疗AD的植物提取化合物最新研究进展(表 2[21-30]3[31-41]), 根据药物调节自噬途径进行分类(表 3)。

Table 2 The effects of polyphenols on autophagy and AD. +: Activation; -: Inhibition; ↑: Enhancement; ↓: Decrease

Table 3 The effects of plant extracts on autophagy and AD. +: Activation; -: Inhibition; ↑: Enhancement; ↓: Decrease

此外, 近年来出现大量研究报道某些天然活性成分可调节自噬, 如多酚类(polyphenols)。富含多酚物质或纯多酚物质被报道通过调节相关途径, 增强自噬清除蛋白质聚集, 起到神经保护和治疗AD作用(表 2)。在少数情况下, 天然酚类物质也被证明能抑制自噬, 或通过自噬相关途径诱导细胞死亡[42, 43], 其中黄酮类(flavonoid)广泛存在于蔬菜、水果等植物中, 近几年研究发现黄酮类化合物具神经保护和诱导自噬作用。在阐述抗AD的多酚类物质文献中, 近年主要报道黄酮类、橄榄苦苷苷元(oleuropein aglycone)、白藜芦醇(resveratrol)和姜黄素(curcumin), 本文按调节自噬途径综述这一类化合物, 为以后研究多酚类抗AD的构效关系提供理论依据。

2.1 经mTOR途径调节自噬的植物提取化合物

从黄岑中分离得到的黄岑素(wogonin)是mTOR分子的抑制剂, 可显著促进原代皮质星形胶质细胞清除Aβ40, 且在原代皮质星形胶质细胞和SH-SY5Y细胞中发现LC3-II积聚, 显示黄岑素可诱导自噬和促进自噬体成熟从而促进Aβ40清除[31]

另外, 原人参二醇(protopanaxadiol derivative, PPD)衍生物DDPU也可经PI3K/AKT/mTOR途径激活自噬, 提高Aβ的清除率, 在治疗AD方面有潜在作用[32]

甲基牛扁亭碱(methyllycaconitine)可能经mTOR途径抑制Aβ25-35诱导的异常自噬, 从而缓解Aβ25-35细胞毒性起到细胞保护作用, 并且甲基牛扁亭碱具有良好的安全性, 表明甲基牛扁亭碱可能是一种抗AD有前景的药物[33]

Li等[34]发现β淀粉样前体蛋白(β-site amyloid precursor protein, APP)/PS1转基因AD鼠模型经雪茶(thamnolia vermicularis)乙醇提取物处理后, mTOR、PI3K和AKT磷酸化水平降低, 而AMPK磷酸化表达上调, 提示雪茶乙醇提取物可作为一个有效自噬激活剂经AMPK/PI3K/AKT/mTOR途径激活自噬促进Aβ清除。另外, 雪茶也作为PI3K抑制剂和AMPK间接激活剂, 抑制PERK/eIF2α途径介导BACE1表达, 从而抑制Aβ产生, 有益于治疗AD。

研究显示, 以转基因AD鼠模型为研究对象, 实验证实牛蒡子苷元(arctigenin)可激活AMPK/Raptor途径和抑制AKT/mTOR途径增强自噬促进Aβ清除[35]

Zhao等[36]发现SH-SY5Y细胞经远志(polygalae)处理后, mTOR和p70s6k表达下调, 显示远志诱导自噬, 进一步研究发现磷酸化AMPK/Raptor水平增加, 提示远志可经AMPK/Raptor/mTOR途径诱导自噬清除Aβ

研究认为, 姜黄素可增强自噬标记蛋白如LC3表达和减少mTOR蛋白表达诱导自噬, 保护细胞免受氧化应激损伤。姜黄素能逆转自噬抑制剂氯喹诱导的自噬抑制, 减少APP转录水平和翻译水平, 通过促进LC3-I向LC3-II转化激活自噬, 还参与自噬-溶酶体系统和APP代谢改善自噬通量。而另一研究发现, 将溶酶体特异性磷酸肌醇PI(3, 5) P2基因或者瞬时受体电位黏蛋白-1基因(transient receptor potential mucolipin-1, TRPML1)敲除后, 姜黄素可抑制由Aβ1-42诱导激活的HT-22细胞mTOR/S6K途径, 显示姜黄素抑制自噬, 这与早期研究结果相反[24, 25], 其机制还需进一步研究。

Kou等[21]发现二氢杨梅素(dihydromyricetin)可上调SIRT1水平和抑制mTOR信号途径从而激活自噬, 并显著逆转AD鼠模型海马神经元自噬功能紊乱。

非瑟酮(fisetin)是一种有机黄酮类天然化合物, 非瑟酮处理AD鼠模型皮层神经元细胞可降低p70S6K和4E-BP1磷酸化水平, 经货物受体(cargo receptor)促进选择性自噬发生, 活化TFEB和Nrf2可诱发自噬和溶酶体基因的表达, 促进磷酸化Tau经自噬得以降解, 且提示非瑟酮可抑制mTORC1活性[22]

2.2 经Bcl-2/Beclin-1途径调节自噬的植物提取化合物

研究发现, 羟基积雪草苷(madecassoside)减少自噬体和炎性因子产生, 增加Bcl-2水平, 降低Beclin-1, 阻断轻链LC3-I向LC3-II转化, 提示羟基积雪草苷可经Beclin-1/Bcl-2途径调节自噬, 从而对Aβ25-35诱导的神经细胞自噬和炎症反应起保护作用[37]

SH-SY5Y细胞经Aβ25-35处理后, β-细辛醚和自噬抑制剂3-甲基腺嘌呤都可逆转Aβ25-35引起的Beclin-1和LC3B水平上升以及抗凋亡蛋白Bcl-2水平下降, 提示β-细辛醚经Beclin-1/Bcl-2途径减轻自噬[38]。对经Aβ1-42处理的PC12细胞施用β-细辛醚后也观察到相同结果[39]。此外, 对APP/PS1转基因AD鼠模型研究发现, β-细辛醚增加p-AKT和p-mTOR水平, 抑制自噬, 提高AD鼠模型空间学习和记忆能力[40]。综上研究, 可认为β-细辛醚可能涉及PI3K/AKT/Beclin-1途径抑制自噬作用, 具有缓解AD症状潜能。

与其他水果和蔬菜相比, 石榴由高浓度多酚组成。APPsw/Tg 2576鼠模型经4%石榴饲料补充15个月后可显著诱导自噬, 表现为Beclin-1、脂质化LC3-II蛋白表达上调、突触可塑性增加以及脑中Aβ沉积减少, 提示石榴在预防AD发生方面可能具有潜在效应[26]

2.3 经自噬-溶酶体途径调节自噬的植物提取药物

由于自噬体最终与溶酶体融合使溶酶体内的蛋白质降解, 因此溶酶体含量可用来评估自噬水平。Li等[41]用自噬抑制剂氯喹处理AD模型蠕虫后, 溶酶体数量显著减少, 抑制蛋白质降解, 阻断自噬过程。随后用重组荞麦胰蛋白酶抑制剂(recombinant buckwheat trypsin inhibitor, rBTI)处理, 溶酶体数目不再下降, 显示rBTI经促进自噬-溶酶体降解途径降低有毒蛋白质和蛋白质聚集体, 缓解Aβ细胞毒性作用, 发挥抗AD作用。

2.4 调节氧化应激水平

NF-κB在氧化应激和神经炎症中扮演着重要的作用, 氧化应激激活时, 胶质细胞产生炎症介导因子COX-2和iNOS; p53是一种肿瘤抑制蛋白, 是调节氧化应激关键因子, 在AD鼠中观察到p53蛋白的增加, 研究表明抑制或消除p53蛋白可诱导自噬。水飞蓟宾(silibinin)是来自草药蓟(水飞蓟)的黄酮类天然化合物, 为水飞蓟素主要药理活性成分。Song等[23]发现大鼠注射Aβ25-35可使海马区自噬水平下调, LC3-I/LC3-II转换率明显降低, p53蛋白水平和炎症介导因子COX-2和iNOS水平显著增加, 自噬体和自噬泡数目减少, 而经水飞蓟宾处理可逆转Aβ25-35作用, 因此水飞蓟宾是治疗AD潜在候选药物。

2.5 其他

橄榄苦苷是多酚类物质中较好的自噬诱导剂, 存在于特级初榨橄榄油中。对迄今为止已知的橄榄苦苷调节自噬途径分类, 有以下3种: ①橄榄苦苷经Ca2+/CaMKK/AMPK/mTOR轴调节自噬。橄榄苦苷增加细胞内Ca2+, 激活Ca2+/CaMKKβ/AMPK轴, 使ULK1形成四元复杂物, 直接或间接抑制mTOR, 从而诱导自噬通量的增加。②橄榄苦苷经PARP1-SIRT1轴调节自噬。橄榄苦苷通过激活SIRT1诱导自噬。③橄榄苦苷作为表观遗传调节剂。橄榄苦苷处理能显著下调组蛋白去乙酰化酶2 (HDAC2)表达[27]。Pantano等[28]发现长期低剂量摄取橄榄油可激活自噬, 即使在晚期AD鼠模型中多酚也显著激活神经元自噬。

雷公藤是一种具有抑制自身炎症作用的中草药, 已被鉴定出含有上百种有效药理活性成分。Xu等[44]发现雷公藤内酯能抑制Aβ25-35诱导的异常自噬增强过程, 降低胞内活性氧水平和LC3-II/LC3-I比例。研究发现雷公藤丁能刺激自噬, 增强细胞活力。随后, 用雷公藤丁处理AD模型鼠3 h或6 h显著增加eGFP-LC3数量, 显示雷公藤丁诱导自噬体形成。雷公藤丁处理3 h后, 细胞中p-mTOR和p70S6K显著降低, 提示雷公藤丁可能抑制mTOR信号通路使自噬激活, 但到目前为止该途径中的特定分子靶标仍不明确[45, 46]

金钗石斛生物碱(Dendrobium nobile Lindl alkaloid)可促进海马神经元自噬体形成和降解增加自噬通量, 诱导大鼠海马神经元自噬[47]。银杏叶提取物(Ginkgo biloba extract)可增加APP转基因AD鼠模型脑中脂质干细胞LC3-II和Beclin-1蛋白水平, 显示自噬增强。研究表明, 小胶质细胞培养过程中经银杏叶提取物处理后LC3-II、Beclin-1和p62蛋白浓度增加, 且长期用银杏提取物处理TgCRND8 APP-转基因鼠观察到自噬激活, 认知功能改善, 提示银杏叶提取物作为一种临床耐受良好的植物提取药物, 长期使用可改善AD病变[48]

最近研究表明, 用Aβ25-35处理PC12细胞后LC3-II/LC3-I比值下降, 用芳基萘基木脂素处理以剂量依赖性方式显著提升比值, 在经Aβ25-35处理前后使用芳基萘基木脂素都显著增加LC3-II表达量, 显示自噬激活[49]。Meng等[50]发现绞股蓝总皂苷也可抑制LC3-I向LC3-II转化, 对抗Aβ25-35诱导的自噬。而另一研究发现, 在AD细胞模型和啮齿动物模型中, 绞股蓝总皂苷激活转录因子EB (transcriptional factor EB, TFEB)经自噬促进Aβ清除, 因此绞股蓝总皂苷虽可缓解AD病理, 但其机制还需进一步确证。

早期报道SIRT1是白藜芦醇一个分子靶点, 白藜芦醇经SIRT1依赖性途径诱导自噬, 减轻Aβ25-35诱导的PC12细胞毒性[29]。研究还发现, 白藜芦醇增加胞内Ca2+水平和促进AMPK第172位点苏氨酸磷酸化激活AMPK, 继而抑制mTOR激活自噬, 发挥抗AD作用[30], SIRT1、AMPK和mTOR依赖途径共同参与白藜芦醇治疗AD病理模型鼠。

3 结语及展望

近几年AD对人类威胁越来越大, 随着药物结构开发、实验技术难题的攻克以及对AD发生的分子机制和相关研究更透彻, 对AD相关药物研究也有一定进展。早期普遍认为, AD患病基于胆碱能假说, 即乙酰胆碱不足是患AD的原因, 随后发现基于此设计的药物只能缓解AD。目前人们更倾向于神经元中毒性蛋白质如Aβ大量聚集、Tau过度磷酸化及自噬异常或不足是患AD的原因。研究发现, 复杂的自噬过程信号转导包括很多途径, 因此发现和设计调节这些途径的药物是目前治疗和预防AD的首要任务。尽管关于AD和自噬研究报道很多, 但还缺乏对某一靶点的深层次阐述。此外, 很多植物提取物是抗AD有希望的候选药物, 因此找到其对应靶点、进行活体实验以及找出其抗AD的构效关系并合成其衍生物还有待进一步研究。

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