内质网是一种多功能的细胞器，在蛋白的分泌、折叠、质量控制、翻译后修饰、Ca2+存储，信号传导等细胞活动中起关键性作用。各种病理生理因素如Ca2+耗竭、氧化应激、通过分泌途径分泌的突变蛋白质等导致非折叠或错误折叠蛋白质在内质网腔中蓄积引起内质网应激(endoplasmic reticulum stress, ER stress)，即内质网内稳态失衡。内质网为重建动态平衡激活非折叠蛋白反应(unfolded protein response, UPR)[1]。内质网稳态失衡可触发ER stress感应器X-盒结合蛋白1(Xbox binding protein-1, XBP1)、PERK (protein kinase RNA like ER kinase)和IRE1α(inositol-requiring enzyme-1alpha)相关的适应性信号级联反应。正常状态下内质网糖调节蛋白(glucose regulated protein 78, GRP78/Bip)与UPR三条主要信号反应通路跨膜蛋白IRE1(inositol-requiring protein-1)、ATF6(activating transcription factor-6)以及PERK结合，使其处于失活状态， ER stress一旦发生，Bip即与未折叠蛋白结合并与这三个蛋白解离，激活这些受体蛋白胞质表面结构，通过增加分子伴侣钙联蛋白(calnexin)、蛋白二硫化物异构酶(protein disulfide isomerase, PDI)、钙网织蛋白(calreticulin)等的表达、减少全局蛋白翻译、增加未折叠/错误折叠蛋白降解并通过内质网相关的降解(ER associated degradation, ERAD)来减轻ER stress、保护细胞[2]。
阿尔茨海默病(Alzheimer's disease, AD)是一种常见的神经退行性病变，以进行性认知功能障碍伴有行为、语言、视觉空间记忆记忆损伤为主要临床症状，最终导致个体过早死亡。尸检神经病理学发现，AD病人大脑皮质和皮质下神经元及突触选择性缺失，细胞外淀粉样蛋白(amyloid β, Aβ)大量堆积，细胞内含有过度磷酸化tau蛋白神经纤维缠结(neurofibrillary tangles, NFT)并发生淀粉样血管病变[3]。研究表明，Aβ干扰内质网功能导致AD患者早期即出现ER stress[4]。同时Aβ可引起原代神经元出现ER stress进而激活线粒体或内质网介导的细胞凋亡[5]。
参考文献
[1] Plácido AI, Pereira CM, Duarte AI, et al. The role of endoplasmic reticulum in amyloid precursor protein processing and trafficking: implications for Alzheimer's disease [J]. Biochimica et biophysica acta, 2014, 1842(9): 1444-1453.
[2] Bernales S, Soto MM, McCullagh E. Unfolded protein stress in the endoplasmic reticulum and mitochondria: a role in neurodegeneration [J]. Frontiers in aging neuroscience, 2012, 4: 5.
[3] Querfurth HW, LaFerla FM. Alzheimer's disease [J]. The New England journal of medicine, 2010, 362(4): 329-344.
[4] Unterberger U，Höftberger R, Gelpi, Ellen, et al. Endoplasmic reticulum stress features are prominent in Alzheimer disease but not in prion diseases in vivo [J]. Journal of neuropathology and experimental neurology, 2006, 65(4): 348-357.
[5] Costa RO, Ferreiro E, Cardoso SM, et al. ER stress-mediated apoptotic pathway induced by Abeta peptide requires the presence of functional mitochondria [J]. Journal of Alzheimer's disease : JAD, 2010, 20(2): 625-636.
（王海云）
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