阿尔茨海默病治疗中相关雌激素信号途径的研究进展

摘要/Abstract

摘要： 阿尔茨海默病（Alzheimer's disease,AD）是一种常见的神经退行性疾病，主要表现为进行性认知功能障碍和记忆力减退。大量临床和流行病学证据表明女性与男性相比有较高的发病率，表明女性更年期雌激素水平下降可能诱发AD。最近的研究提出雌激素可以直接减少细胞外β-淀粉样蛋白形成的老年斑和Tau蛋白过度磷酸化形成的神经原纤维缠结，这两种AD的显著病理特征。大量实验证实雌激素具有神经保护作用，但绝经后女性的临床试验表明雌激素对AD的影响并不明显，这可能与雌激素受体选择性相关。本文就近年来雌激素及其ERα或ERβ受体与AD间的研究进行综述，进一步讨论雌激素受体选择性配体作为AD治疗中安全、有效的靶点。

关键词: 雌激素, 雌激素受体, 阿尔茨海默病

Abstract: Alzheimer's disease(AD) is a common neurodegenerative diseases,and main symptomsare progressive cognitive dysfunction and memory deteriora -tion.Numerous clinical and epidemiological studies show that there is a gender difference in the incidence of AD,women are more likely to develop AD post-menopause,indicating the lack of estrogen is a risk factor of AD.Recent research has proposed estrogen can directly reduce the accumulation of senile plaqueand neurofibrillarytangles, the two significant pathological characteristics of AD. Studies have showed that estrogen may has neuroprotective effects,while clinical trials of women post-menopausal show no obvious effects of estrogen on AD.The discrepancies may related to the selectivity of estrogen receptors.This review will make a brief summary on AD related estrogen and estrogen receptors such as ER alpha or ER beta subtype,further discussing selective ligands of estrogen receptors provided a safe and effective treatment to AD.

Key words: estrogen, estrogen receptor, Alzheimer's disease

刘杨，沈丽霞. 阿尔茨海默病治疗中相关雌激素信号途径的研究进展[J]. 神经药理学报, 2015, 5(4): 43-54.

LIU Yang, SHEN Li-Xia. Research Progress of Estrogen Signal Pathway in Alzheimer’s Disease[J]. Acta Neuropharmacologica, 2015, 5(4): 43-54.

参考文献

[1]Alzheimer’s Disease International. World Alzheimer report 2015[EB/OL]. [2015-09-23].http://www.worldalzreport2015.org.

[2]Michael C Craig, D G Murphy. Estrogen therapy and Alzheimer’s dementia. [J]. Annals New York Academy Sciences, 2010, 1205: 245-253.

[3]Buy J N, Ghossain M. Ovarian and adrenal hormonal synthesis[M].Berlin Heidelberg: Springer-Verlag, 2013: 47-49.

[4]Whitney Wharton, Laura D Baker, Carey E Gleason, et al. Short-term hormone therapy with transdermal estradiol improves cognition for postmenopausal women with Alzheimer's disease: results of a randomized controlledtrial[J]. J Alzheimer’s Disease, 2011, 26(3): 495–505.

[5]Marc Robinson-Rechavi, Hector Escriva Garcia, Vincent Laudet. The nuclear receptor superfamily [J]. J Cell Science, 2003, 116(4): 585-586.

[6]Hinrich Gronemeyer, Jan-Ake Gustafsson, Vincent Laudet. Principles for modulation of the nuclear receptor superfamily[J].Nature reviews drug discovery, 2004, 3(11): 950-964.

[7]Stefan Nilsson, Sari Makela, Eckardt Treuter, et al. Mechanisms of estrogenaction[J].Physiological Rev, 2001, 81(4):1535-1565．

[8] Eric R Prossnitz, Jeffrey B Arterburn, Larry A Sklar. GPR30:A G protein-coupled receptor for estrogen[J].Molecular and cellular Endocrinology, 2007, 265-266:138-142.

[9]Dennis J Selkoe. Alzheimer'sdisease: genes, proteins, and herapy[J].Physiological Rev, 2001, 81(2):741–766.

[10]李林.中国阿尔茨海默病研究进展[J].中国药理学与毒理学杂志, 2015, 29(5): 765-783.

[11]陈红, 赵鹏, 孙亚平, 等. 阿尔茨海默病发病机制研究进展[J].生物技术世界, 2015, 10: 99-100.

[12]邸云峰, 韦丽华, 焦玉蓉, 等. Tau蛋白过度磷酸化诱导Aβ生成抑制THP-1 细胞ABCAl的表达[J].四川生理科学杂志, 2010, 32(2): 63-66.

[13]Armstrong R A. The pathogenesis of Alzheimer's disease:are evaluation of the “amyloid cascade hypothesis”[J].J Int Alzheimer's Disease, 2010, 2011(2011):630865.

[14]Giannakopoulos P, Francois Herrmann, Bussiere T, et al. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer's disease[J].Neurology, 2003, 60(9):1495–1500.

[15] Shao Wen-lin, Myles Brown. Advances in estrogen receptor biology: prospects for improvements in targeted breast cancer therapy[J].Breast Cancer Research, 2004, 6(1):39-52.

[16]沈丽霞, 张力. 雌激素神经保护作用研究进展[J].神经药理学报, 2012, 2(3): 29-36.

[17]贵春山, 沈建华, 罗小民, 等. 雌激素受体和选择性雌激素受体调节剂的研究进展[J]. 中国药物化学杂志, 2005, 15(5): 313-320.

[18]Sumito Ogawa, Satoshi Inoue, Toru Watanabe, et al. The complete primary structure of human estrogen receptor beta(hER beta) and its heterodimerization with ER alpha in vivo and in vitro[J].Biochemical and Biophysical Research Communications, 1998, 243(1): 122 -126.

[19]Sandra Pearce, V Craig Jordan. The biological role of estrogen receptors alpha and beta in cancer[J].Critical Reviews in Oncology/Hematology, 2004, 50(1): 3-22.

[20]Leigh Murphy, Tracy Cherlet, Anthony Lewis, et al. New insights into estrogen receptor function in human breast cancer[J].Annals of Medicine, 2003, 35(8): 614-631.

[21]Rollerova E, Urbancikova M. Intracelluar estrogen receptors, their characteri- zation and function[J].Endocrine Regulations, 2000, 34(4): 203-218.

[22]Hinrich Gronemeyer, Jan-Ake Gustafsson, Vincent Laudet. Principles for modulation of the nuclear receptor superfamily[J].Nature Rev Drug Discovery, 2004, 3(11): 950-964.

[23]Rochette-Egly Cécile. Dynamic combinatorial networks in nuclear receptor-mediated transcription[J].J Biological Chemistry, 2005, 280(38):32565–32568.

[24]Lee Jung Hoon, Yanxialei Jiang, Dong Hoon Han, et al. Targeting estrogen receptorsfor the treatment of Alzheimer’s disease[J].Molecular Neurobiology,2013,49(1):1-11.

[25] Chetana M Revankar, Daniel F Cimino, Larry A Sklar, et al. A transmembrane intracellular estrogen receptor mediates rapid cell signaling[J].Science, 2005, 307(5715): 1625-1630.

[26]Matthias R Meyer, Elvira Haas, Eric R Prossnitz, et al. Non-genomic regulation of vascular cell function and growth by estrogen[J].Molecular Cellular Endocrinology, 2009, 308(1-2): 9-16．

[27]Mermelstein P G, Jill B Becker, Dalton James Surmeier. Estradiol reduces calcium currents in rat neostriatal neurons via a membrane receptor[J]. J Neuroscience, 1996, 16(2): 595-604.

[28]Filardo E J, Quinn J A, Frackelton AR Jr, et al. Estrogen action via the G protein -coupled receptor, GPR30: stimulation of adenylyl cyclase and cAMP mediated attenuation of the epidermal growth factor receptor-to-MAPK signaling axis[J].J Molecular Endocrinology, 2002, 16(1): 70–84.

[29]Soraya L Vallés, Consuelo Borrás, Juan Gambini, et al. Oestradiol or genistein rescues neurons from amyloid beta-induced cell death by inhibiting activation of p38[J]. AgingCell, 2008, 7(1): 112-118．

[30]党惠子, 李瑞晟, 王虹, 等. 姜黄素对APP/PS1双转基因小鼠海马PI3K及p-PI3K表达的影响[J].中国中药杂志, 2013, 38(9): 1295-1298.

[31]Filice E, Anna Grazia Recchia, Daniela Pellegrino, et al. A new membrane G protein coupled receptor (GPR30) is involved in the cardiac effects of17β-estradiol the male rat[J].J Physiology Pharmacology, 2009, 60(4): 3–10.

[32] Christina M Doolan, Steven B Condliffe, Brian J Harvey. Rapid non-genomic activation of cytosolic cyclic AMP-dependent protein kinase activity and [Ca(2+)](i) by 17beta-oestradiol in female rat distal colon[J].British J Pharmacology, 2000, 129(7): 1375–1386.

[33]谢贵花, 潘小玲, 李慧, 等. 雌激素与老年性痴呆关系的研究进展[J].南昌大学学报: 医学版, 2014, 54(10): 88-92.

[34]Elisabetta De Marinis, Paolo Ascenzi, Marco Pellegrini, et al. 17β-estradiol a new modulator of neuroglobin levels in neurons:role in neuroprotection against H2O2-Induced toxicity [J].Neurosignals, 2010, 18(4): 223-235．

[35]Csoregh Nord L, Sundqvist J, Andersson E, et al. Analysis of oestrogen regulation of alpha-,beta- and gamma-secretase gene and protein expression in cultured human neuronal and glial cells[J].Neurodegener Diseases, 2012, 7(6): 349–364.

[36]Yue Xu, Melissa Lu, Techie Lancaster, et al. Brain estrogen deficiency accelerates Abeta plaque formation in an Alzheimer's disease animal model[J].Proceedings of the National Academy of Sciences USA, 2005, 102(52): 19198-19203.

[37]Zhang She-qing, Darrell Sawmiller, Li Song, et al. Octyl gallate markedly promotes anti-amyloidogenic processing of APP through estrogen receptor-mediated ADAM10 activation[J].Plos One, 2013, 8(8):800-802.

[38]Roberta Diaz Brinton. The healthy cell bias of estrogen action: mitochondrial bioenergetics and neurological implications[J].Trends in Neurosciences, 2008, 31(10): 529-537.

[39]Christian J Pike, Jenna C Carroll, Emily R Rosario, et al. Protective actions of sex steroid hormones in Alzheimer’s disease[J].Frontiers in Neuroendocrinology, 2009, 30(2): 239-258.

[40]Zhao Li-qin, Roberta Diaz Brinton. Estrogen receptor alpha and beta differentially regulate intracellular Ca(2+) dynamics leading to ERK phosphorylation and estrogen neuroprotection in hippocampal neurons[J].Brain Research, 2007, 1172(1): 48-59.

[41]Igor V Kurochkin. Insulin-degrading enzyme: embarking on amyloid destruction[J].Trends in Biochemical Sciences, 2001, 26(7): 421-425.

[42]Dennis J Selkoe. Clearing the brain’s amyloid cobwebs[J].Neuron, 2001, 32(2): 177-180.

[43]Qiu Wei-qiao, Marshal F Folstein. Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer's disease: review and hypothesis[J]. Neurobiol Aging, 2006, 27(2): 190-198.

[44]Anusha Jayaraman, Jenna C Carroll, Todd E Morgan, et al. 17beta-estradiol and progesterone regulate expression of betaamyloid clearance factors in primary neuron cultures and female rat brain[J].Endocrinology, 2012, 153(11): 5467–5479.

[45]Liqin Zhaoa, Jia Yao a, ZisuMaoa, et al.17β-Estradiol regulates insulin degarding enzyme expression via an ERβ/PI3-K pathway in hippocampus: relevance to Alzheimer’s prevention[J].Neurobiology of Aging, 2011, 32(11): 1949-1963.

[46]Wesley Farris, Sonja G Schutz, John R Cirrito, et al. Loss of neprilysin function promotes amyloid plaque formationand causes cerebral amyloid angiopathy[J]. American J Pathology, 2007, l171(1): 241–251.

[47]Liang Kai-wei, Yang Liu-qing, Yin Can-ben, et al. Estrogen stimulater degradation of β-amyloid peptide by up-regulating neprilysin[J]. J Biological Chemistry, 2010, 285(2): 935-942.

[48]Sonia George, Geraldine H Petit, Gunnar K Gouras, et al. Nonsteroidal selective androgen receptor modulators and selective estrogen receptor β agonists moderate cognitive deficitsand amyloid-β levels in a mouse model of Alzheimer's disease[J]. ACS Chemical Neuroscience, 2013, 4(12): 1537-1548.

[49]Yin Ke-jie, John R Cirrito, Yan Ping, et al. Matrix metallo proteinases expressed by astrocytes mediate extracellular amyloid-beta peptide catabolism[J].J Neuroscience, 2006, 26(43): 10939–10948.

[50]Callum S Wingrove, Edmund Garr, Ian F Godsland, et al. 17β-oestradiol enhances release of matrix metalloproteinase-2 from human vascular smooth muscle cells[J]. Biochimicaet Biophysica Acta, 1998, 1406(2): 169–174.

[51]Sara Merlo, Maria Angela Sortino. Estrogen activates matrix metalloproteinases-2 and -9 to increase beta amyloid degradation[J].Molecular and Cellular Neuroscience, 2012, 49(4): 423-429.

[52]Min Jae Lee, Jung Hoon Lee, David C Rubinsztein. Tau degradation:The ubiquitin–proteasome system versus the autophagy-lysosome system[J].Progress in Neurobiology, 2013, 105(6): 49-59.

[53]Paul S Aisen. Alzheimer's disease therapeutic research: the path forward[J].Alzheimer's Research & Therapy, 2009, 1(1): 2.

[54]Claudie Hooper, Richard Killick, Simon Lovestone. The GSK3 hypothesis of Alzheimer’s disease[J]. J Neurochemistry, 2008, 104(6): 1433-1439.

[55]Shi Hai-rong, Zhu Ling-qiang, Wang Shao-hui, et al. 17beta-estradiol attenuates glycogen synthase kinase-3beta activation and tau hyperphosphorylation in Akt-independent manner[J].J Neural Transmission, 2008, 115(6): 879-888．

[56]Zhang Quan-guang, Wang Rui-min, Khan Mohammad, et al. Role of Dickkopf-1,an antagonist of the Wnt/beta-catenin signaling path-way,in estrogen-induced Neuroprotection and attenuation of tau phosphorylation[J]. J Neuroscience, 2008, 28(34): 8430-8441.

[57]Liu Xin-an, Zhu Ling-qiang, Zhang Qi, et al. Estradiol attenuates tau hyperphosphorylation induced by upregulation of protein kinase-A[J].Neurochem Research, 2008, 33(9): 1811-1820.

[58]Anat Boehm, Ori Liraz, D M Michaelson. ApoE4 induces A beta 42,tau,and neural pathology in the hippocampus of young targeted replacement apoE4 mice[J]. J Molecular Neuroscience, 2013, 8: 16.

[59]Rachelle Crescenzi, Catherine Debrosse, Ravi Prakash Reddy Nanga, et al. In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy[J].Neuroimage, 2014, 101(1): 185-192.

[60]Burbaeva G S, Boksha I S, Tereshkina E B, et al. A role of glutamate decarboxy-lase in Alzheimer’s disease[J].Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova, 2014, 114(4): 68–72.

[61]Fabiola M Ribeiro, Rebecca A Devries, Alison Hamilton, et al. Metabotropic glutamate receptor 5 knockout promotes motor and biochemical alterations in a mouse model of Huntington’s disease[J].Human Molecular Genetics, 2014, 23(8): 2030–2042.

[62]Gingerich S, Kim G L, Chalmers J A, et al.Estrogen receptor alpha and G-proteincoupled receptor 30 mediate the neuroprotective effects of 17beta-estradiol in novel murine hippocampal cell models[J].Neuroscience, 2010, 170(1): 54–66.

[63]Eunsook Lee, Marta Sidoryk-Wegrzynowicz, Ning Wang, et al. GPR30 regulates glutamate transporter GLT-1 expression in rat primary astrocytes[J].J Biological Chemistry, 2012, 287(32): 26817-26828.

[64]Eunsook Lee, Marta Sidoryk-Wegrzynowicz, Zhao-bao Yin, et al. Transforming growth factor-α mediates estrogen-induced upregulation of glutamate transporter GLT-1 in rat primary astrocytes[J].Glia, 2012, 60(7): 1024-36.

[65]Olga Lipatova, Dennis Byrd, John T Green, et al. Effects of continuous vs.cycling estrogen replacement on the acquisition,retention and expression of place- and response-learning in the open-field tower maze[J].Neurobiology of Learning &Memory, 2014, 114(9): 81-89.

[66]Eva M Szego, Klaudia Barabas, Julia Balog, et al. Estrogen induces estrogen receptor alpha-dependent cAMP response elementbinding protein phosphorylatio via mitogen activated protein kinase pathway in basal forebrain cholinergic neurons in vivo[J]. J Neuroscience, 2006, 26(15): 4104–4110.

[67]Mermelstein P G. Membrane-localised oestrogen receptor alpha and beta influence neuronal activity through activation of metabotropic glutamate receptors[J].J Neuroendocrinology, 2009, 21(4): 257–262.

[68]Marissa I Boulware, Jason P Weick, Bryan R Becklund, et al. Estradiol activates group I and II metabotropic glutamate receptor signaling,leading to opposing influences on cAMP response elementbinding protein[J]. J Neuroscience, 2005, 25(20): 5066–5078.

[69]Marissa I Boulware, Paul G Mermelstein. Membrane estrogen receptors activate metabotropic glutamate receptors to influence nervous system physiology[J].Steroids, 2009, 74(7): 608–613.

[70]李兴宇, 高灿. 突触上与突触外的NMDA受体及其与阿尔茨海默病关系的研究进展[J].生物化学与生物物理进展, 2014, 41(9): 823-829.

[71]Yu-Long Lan, Jie Zhao, Shao Li. Estrogen receptors’neuroprotective effect againstglutamate-induced neurotoxicity[J].Neurological Sciences, 2014, 35(11): 1657-1662

[72]Al-Sweidi S, Morissette M, Di Paolo T. Effect of oestrogen receptors on brain NMDA receptors of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice[J]. J Neuroendocrinology, 2012, 24(11): 1375-1385.

[73]Damani N Bryant, Daniel M Dorsa. Roles of estrogen receptors alpha and beta in sexually dimorphic neuroprotection against glutamate toxicity[J].Neuroscience, 2010, 170(4): 1261–1269.

[74]Claudia Aguirre, Anusha Jayaraman, Christian Pike, et al. Progesterone inhibitsestrogen mediated neuroprotection against excitotoxicity by down-regulating estrogen receptor-beta[J].J Neurochemistry, 2010, 115(5): 1277–1287.

[75]Liu Ning, Shang Jing-wei, Tian Feng-feng, et al. In vivo optical imaging for evaluating the efficacy of edaravone after transient cerebral ischemia in mice[J].Brain Research, 2011, 1397(6): 66-75.

[76]Jesper Riise, Niels Plath, Bente Pakkenberg, et al. Aberrant Wnt signaling pathway in medial temporal lobe structures of Alzheimer’s disease[J].Neurologyand Preclinical Neurological Studies, 2015, 122(9): 1303-1318.

[77]陈雪, 孙婧霞, 蒋常文. Bcl-2、Caspase-3与阿尔茨海默病关系的研究进展[J].临床医学工程, 2013, 20(9): 1177-1179.

[78]Suparna Mazumder, Dragos Plesca, Alexandru Almasan. Caspase-3 activation is a critical determinant of genotoxic stress-induced apoptosis[J].Methods in Molecular Biology, 2008, 414(414): 13-21.

[79]Roberta Visconti, Luciano D'Adamio. Functional cloning of genes regulating apoptosis in neuronal cells[J].Methods in Molecular Biology, 2007, 399: 125-131.

[80]Ling-Min Li, Qing-Hua Liu, Jian-Tian Qiao, et al. Aβ31-35-induced neuronal apoptosis is mediated by JNK-dependent extrinsic apoptosispathway[J].Neuroscience Bulletin, 2009, 25(6): 361-366.

[81]Stephen R Hammes, Ellis R Levin. Extranuclear steroid receptors: nature and actions[J].Endocrine Reviews, 2007, 28(7): 726-741.

[82]Yun Peng, Bo Jiang, Huiling Wu, et al. Effects of genistein on neuronal apoptosis,and expression of Bcl-2 and Bax proteins in the hippocampus of Ovariectomizedrats[J].Neural Regeneration Research, 2012, 7(36): 2874-2881.

[83]张雪玲, 齐晓岚, 单可人. 阿尔茨海默病中β淀粉样蛋白与MAPK信号通路的关系[J].中国老年学杂志, 2011, 31(13): 2589-2591.

[84]Scott M Belcher, Attila Zsarnovszky. Estrogenic actions in the brain: estrogen, phytoestro-gens, and rapid intracellular signaling mechanisms[J].J Pharmacology&Experimental Therapeutics, 2001, 299(2): 408-414.

[85]EHC Falkenstein, Tillmann H C, Christ M, et al. Multiple actions of steroid hormones-A focus on rapid, nongenomic effects[J].Pharmacological Reviews, 2000, 52(4): 513-556.

[86]Jeremy P E Spencer. The interactions of flavonoids within neuronal signalling pathways[J].Genes & Nutrition, 2008, 2(3): 257-73.

[87]Shang Yong-feng, Myles Brown. Molecular determinants for the tissue specificity of SERMs[J].Science, 2002, 295(5564): 2465-2468.

[88]Sarah C Janicki, Nicole Schupf. Hormonal influences on cognition and risk for Alzheimer's disease[J].Current Neurology&Neuroscience Reports, 2010, 10(5): 359-66.

[89]Simona Federica Spampinato, Gemma Molinaro, Sara Merlo, et al. Estrogen receptors and type 1 metabotropic glutamate receptors are interdependent in protecting cortical neurons against beta-amyloid toxicity[J].Molecular Pharmacology, 2012, 81(1): 12–20.

[90]Jenna C Carroll, Christian J Pike. Selective estrogen receptor modulators differentially regulate Alzheimer-like changes in female 3xTg-AD mice[J].Endocrinology, 2008, 149(5): 2607–2611.

[91]Maryam Bagheri, Mohammad-Taghi Joghataei, Simin Mohseni, et al. Genistein ameliorates learning and memory deficits in amyloid beta(1-40) rat model of Alzheimer's disease[J]. Neurobiology of Learning and Memory, 2011, 95(3): 270–276.

[92]Amandine Grimm, Lim Yun-an, Ayikoe Guy Mensah-Nyagan, et al. Alzheimer's disease, oestrogen and mitochondria: an ambiguous relationship[J].Molecular Neurobiology, 2012, 46(1): 151–160.

[93]Laura H Coker, Mark A Espeland, Stephen R Rapp, et al. Postemenopausal hormone therapy and cognitive outcomes: the Women’s Health Initiative Memory Study(WHIMS)[J]. J Steroid Biochemistry and Molecular Biology, 2010, 118(118): 304-310.　

[94]Rachel A Whitmer, Charles P Quesenberry, Zhou Ju-fen, et al. Timing of hormone therapy and dementia: the critical window theory revisited[J].Ann Neurology, 2011, 69(1): 163-169.