<strong>脂肪因子参与阿尔茨海默病的研究进展</strong>

神经药理学报››2017,Vol. 7››Issue (1): 45-52.DOI:10.3969/j.issn.2095-1396.2017.01.006

脂肪因子参与阿尔茨海默病的研究进展

罗飘，楚世峰，陈乃宏

1. 湖南中医药大学药学院，长沙，410208，中国
2. 中国医学科学院，药物研究所 & 神经科学中心，北京，100050，中国

出版日期:2017-02-26发布日期:2017-12-01
通讯作者:陈乃宏，男，博士，研究员，博士生导师；研究方向：神经系统疾患创新药物开发及作用机制；E-mail：chennh@ imm.ac.cn
作者简介:罗飘，男，硕士研究生；研究方向：神经药理学和中药药理学；E-mail：luopiao168@163.com
基金资助:

国家自然科学基金项目（No.81274122、81373997、81273629、21272278、U1402221、81260650），北京市自然科学基金项目（No.7131013 7142115），湖南省重点研发计划项目（No. 2015SK2029-1），湖南省教育厅高校科研经费开放基金项目（No.15K091），新药作用机制研究与药效评价北京市重点实验室资助项目（No.BZ0150）

Progress on Adipokines Participating in Alzheimer’s Disease

LUO Piao，CHU Shi-feng，CHEN Nai-hong

1. College of Pharmacy，Hunan University of Chinese Medcine，410208，China
2. Neuroscience Center，Institute of Materia Medica，Chinese Academy of Medical Sciences and Peking Union Medical College，Beijing，100050，China

Online:2017-02-26Published:2017-12-01
Contact:陈乃宏，男，博士，研究员，博士生导师；研究方向：神经系统疾患创新药物开发及作用机制；E-mail：chennh@ imm.ac.cn
About author:罗飘，男，硕士研究生；研究方向：神经药理学和中药药理学；E-mail：luopiao168@163.com
Supported by:

国家自然科学基金项目（No.81274122、81373997、81273629、21272278、U1402221、81260650），北京市自然科学基金项目（No.7131013 7142115），湖南省重点研发计划项目（No. 2015SK2029-1），湖南省教育厅高校科研经费开放基金项目（No.15K091），新药作用机制研究与药效评价北京市重点实验室资助项目（No.BZ0150）

摘要/Abstract

摘要：阿尔茨海默病（Alzheimer’s disease，AD）又称老年痴呆，是一种最常见的老年中枢神经退行性疾病。其主要病理改变有：神经元外β- 淀粉样蛋白（β-amyloid protein，Aβ）沉积形成的老年斑、神经元内tau 蛋白异常磷酸化形成的神经原纤维缠结以及神经元大量丢失或损伤。近年研究发现，脂肪因子与Aβ沉积、tau 蛋白过度磷酸化以及神经元凋亡之间具有紧密的联系。该文主要针对脂联素（adiponectin，APN）、瘦素（leptin，LP）、白细胞介素-6（interleukin-6，IL-6）等脂肪因子对AD 的作用机制做一综述，为AD 的临床治疗提供新的思路。

关键词:阿尔茨海默病,脂肪因子,脂联素,瘦素,白细胞介素-6

Abstract:Alzheimer’s disease（AD），also called senile dementia，is one of the most common central neurodegenerative disease in the elderly. And its main pathological changes include the senile plaques formed by β-amyloid protein deposition out of the neuron， neurofibrillary tangles caused by the hyperphosphorylated tau protein in the neuron，and neurons in large number of loss and damage. Recently，the study has showed that Adipokine has closed relationship between β-amyloid protein deposition，hyperphosphorylated tau protein and neuronal apoptosis. This paper is mainly about the effect and mechanism of Adipokine，such as adiponectin，leptin，interleukin-6 and so on，on AD，which aims to provide a new ideas for the clinical treatment of AD.

Key words:Alzheimer&,rsquo,s disease,adipokine,adiponectin,leptin,interleukin-6

中图分类号:

R964

罗飘，楚世峰，陈乃宏.脂肪因子参与阿尔茨海默病的研究进展[J]. 神经药理学报, 2017, 7(1): 45-52.

LUO Piao，CHU Shi-feng，CHEN Nai-hong.Progress on Adipokines Participating in Alzheimer’s Disease[J]. Acta Neuropharmacologica, 2017, 7(1): 45-52.

参考文献

[1] Huang Han-chang, Jiang Zhao-feng. Accumulated amyloid-βpeptide and hyperphosphorylated tau protein: Relationship and links in Alzheimer's disease[J]. J Alzheimers Dis, 2009, 16(1): 15- 27.

[2] James Shearer, Colin Green, Craig W Ritchie, et al. Health state values for use in the economic evaluation of treatments for Alzheimer's disease [J].Drugs Aging, 2012, 29(1): 31-43.

[3] Shi Hua, Wang Zhen. A brief review on studies of Alzheimer's disease in China: its mechanism, imaging and therapy[J].Sci China Life Sci, 2013, 56(12): 1142-1144.

[4] Mitsuru Shinohara, Shinsuke Fujioka, Melissa E Murray, et al. Regional distribution of synaptic markers and APP correlate with distinct clinicopathological features in sporadic and familial Alzheimer's disease[J].Brain, 2014, 137(5): 1533-1549.

[5] Wang Jun, Bi Wen-na, Alice Cheng, et al. Targeting multiple pathogenic mechanisms with polyphenols for the treatment of Alzheimer's disease-experimental approach and therapeutic implications [J].Front Aging Neurosci, 2014, 6: 42.

[6]刘琼珍, 吕文婷, 蔡旻煊, 等. 代谢性疾病对情绪和认知功能的影响及其可能机制研究进展[J].中国药理学与毒理学杂志, 2015, 29(5): 847-858.

[7]Jaume Folch, Ivan Patraca, Nohora Martínez, et al. The role of leptin in the sporadic form of Alzheimer's disease. Interactions with the adipokines amylin, ghrelin and the pituitary hormone prolactin[J].Life Sci, 2015, 140(11): 19-28.

[8]王晓芳, 丁维俊. 肥胖引起阿尔茨海默病的机制探讨[J].中国老年保健医学, 2015, 13(2): 102-104.

[9] Steven J Greco, Ashkan Hamzelou, Jane M Johnston, et al. Leptin boosts cellular metabolism by activating AMPK and the sirtuins to reduce tau phosphorylation and β-amyloid in neurons [J]. Biochem Biophys Res Commun, 2011, 414(1):170-174.

[10] Rocio Pérez-González, Desiree Antequera, Teo Vargas, et al. Leptin induces proliferation of neuronal progenitors and neuroprotection in a mouse model of Alzheimer's disease [J].J Alzheimers Dis, 2011, 24(2):17-25.

[11] Steven J Greco, Kathryn J Bryan, Sraboni Sarkar, et al. Leptin reduces pathology and improves memory in a transgenic mouse model of Alzheimer's disease [J]. J Alzheimers Dis, 2010, 19(4): 1155-1167.

[12] Wolfgang Lieb, Alexa S Beiser, Ramachandran S Vasan, et al. Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging [J].JAMA, 2009, 302(23): 2565-2572.

[13]Jane M Johnston, William T Hu, David Fardo, et al. Low plasma leptin in cognitively impaired ADNI subjects: gender differences and diagnostic and therapeutic potential [J].Curr Alzheimer Res, 2014, 11(2): 165-174.

[14] Karen F Holden, Karla Lindquist, Frances A Tylavsky, et al. Serum leptin level and cognition in the elderly: Findings from the Health ABC Study [J].Neurobiol Aging, 2009, 30(9): 1483-1489.

[15] Gayle H Doherty, Dayne Beccano-Kelly, Yan Shi-dan, et al. Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid β[J].Neurobiol Aging, 2013, 34(1), 226-237.

[16] Silvia Maioli, Maria Lodeiro, Paula Merino-Serrais, et al. Alterations in brain leptin signalling in spite of unchanged CSF leptin levels in Alzheimer's disease [J].Aging Cell, 2015, 14(1): 122-129.

[17]Charlotte Teunissen, Wiesje M van der Flier, Ph Scheltens, et al. Serum Leptin is not Altered nor Related to Cognitive Decline in Alzheimer's Disease [J].J Alzheimers Dis, 2015, 44(3): 809-813.

[18]Folch J1, Patraca I1, Martínez N,et al.The role of leptin in the sporadic form of Alzheimer's disease. Interactions with the adipokines amylin, ghrelin and the pituitary hormone prolactin [J].Life Sci, 2015 ,140(1):19-28. 与7重复

[19] Gurdeep Marwarha, Bhanu Dasari, Jaya R P Prasanthi, et al. Leptin reduces the accumulation of Abeta and phosphorylated tau induced by 27-hydroxycholesterol in rabbit organotypic slices[J].J Alzheimers Dis, 2010, 19(3): 1007-1019.

[20]Darius C Fewlass, Karina Noboa, Xavier Pi-Sunyer, et al. Obesity-related leptin regulates Alzheimer's Abeta [J]. FASEB J, 2004 ,18(15):1870-1878.

[21] Dana M Niedowicz, Christa M Studzinski, Adam M Weidner, et al. Leptin regulates amyloid β production via theγ-secretase complex [J].Biochimica et Biophysica Acta, 2013, 1832(3): 439-444.

[22] Cheng Xiao-fang, Wu Jian, Geng Miao, et al. The role of synaptic activity in the regulation of amyloid beta levels in Alzheimer 's disease [J].Neurobiol Aging, 2014, 35(6): 1217-1232.

[23]Jochen Seufen, Timothy J Kieffer, Colin A Leech, et al. Leptin suppression of insulin secretion and gene expression in human pancreaticislets: implications for the development of adipogenic diabetes mellitus [J].J Clin Endocrinol Metab, 1999, 84(2): 670-676.

[24]Baumann K, Mandelkow E M, Biernat J, et al. Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin- dependent kinases cdk2 and cdk5[J]. FEBS Lett, 1993, 336(3): 417-424.

[25]Jean C Augustinack, Judith L Sanders, Li-Huei Tsai, et al. Colocalization and fluorescence resonance energy transfer between cdk5 and AT8 suggests a close association in pre-neurofibrillary tangles and neurofibrillary tangles[J] J Neuropathol Exp Neurol, 2002, 61(6): 557-564.

[26]梁辰. 瘦素经Cdk5途径改善阿尔茨海默病样tau蛋白过度磷酸化的研究[D].北京：中国人民解放军医学院, 2013.

[27]Claudie Hooper, Richard Killick, Simon Lovestone. The GSK3 hypothesis of Alzheimer's disease [J].J Neurochem. 2008; 104(6):1433-1439.

[28]Jihoon Jo, Daniel J Whitcomb. Aβ(1-42) inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3β[J].Nat Neurosci, 2011, 14(5): 545-547.

[29] Oomura Y, Aou S, Fukunaga K, et al. Prandial increases of leptin and orexin in the brain modulate spatial learning and memory [J]. Ross Fiziol Zh Im I M Sechenova, 2009, 95(12): 1373-1385.

[30] Ganesh M Shankar, Li Shao-min, Tapan H Metha, et al. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory [J]. Nat Med, 2008 ,14(8): 837-842.

[31] Andrew J Irving, Jenni Harvey. Leptin regulation of hippocampal synaptic function in health and disease [J].Philos Trans R Soc B Biol Sci, 2013, 369(1633): 20130155.

[32] Dayne Beccano-Kelly, Jenni Harvey. Leptin: a novel therapeutic target in Alzheimer's disease?[J].Int J Alzheimers Dis, 2012, 2012: 594137.

[33] Enrique Z Fisman, Alexander Tenenbaum. Adiponectin: a manifold therapeutic target for metabolic syndrome,diabetes,and coronary disease? [J].Cardiovasc Diabetol, 2014, 13: 103.

[34]K Une, Asako Takei, N Tomita. Adiponectin in plasma and cerebrospinal fluid in MCI and Alzheimer's disease[J]. Eur J Neurol, 2011, 18(7): 1006-1009.

[35]Antonio L Teixeira, Breno S Diniz, Alline C Campos, et al. Decreased levels of circulating adiponectin in mild cognitive impairment and Alzheimer's disease[J].Neuromolecular Med, 2013, 15(1): 115-121.

[36]Yu Zhu-ling, Li Wei, Deren Hou, et al. Relationship between adiponectin genen polymorphisms and late-onset Alzheimer's disease[J].PLoS One, 2015, 10(4): e0125186.

[37]徐志鹏, 黎红华, 武强, 等. 阿尔茨海默病患者血浆脂联素与Aβ水平的变化[J].Stroke Nervous Disease, 2016, 23(1): 5-8.

[38]Gerhild Echten-Decker, Jochen Walter. Sphingolipids: critical players in Alzheimer's disease[J].Prog Lipid Res, 2012, 51(4): 378-393.

[39] 宋哲, 薛超, 张小曼, 等. 脂联素通过激活PP2A减轻H2O2诱导的SH-SY5Y细胞损伤及tau蛋白过度磷酸化[J].中国病理生理杂志, 2015, 31(2): 207-212.

[40] Leroy K, Yilmaz Z, Brion J P. Increased level of active GSK-3β in Alzheimer's disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration[J].Neuropathol Appl Neurobiol, 2007, 33(1): 43-55.

[41] Gong Cheng-xin, Sadia Shaikh, Wang Jian-zhi, et al. Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain[J].J Neurochem, 1995, 65(2): 732-738.

[42]Qiu Guang, Wan Rui-qian, Hu Jing-ping, et al. Adiponectin protects rat hippocampal neurons against excitotoxicity [J].Age(Dordr), 2011, 33(2): 155-165.

[43] Takayuki Masaki, Futoshi Anan, Hironobu Yoshimatsu. Decreased high molecular weight adiponectin in sera is associated with white matter lesions in Japanese men with type 2 diabetes[J].Diabetes Care, 2011, 34(8): e132.

[44]尹泽钢. 代谢综合征、血脂水平和脂联素基因多态性与脑白质病变关系的研究[D].重庆：第三军医大学, 2014.

[45]周世明. 吸烟、饮酒及脂联素基因多态性与阿尔茨海默病发生的关系[D].重庆: 第三军医大学, 2014.

[46]Andreas Schäffler, Jurgen Schölmerich. Innate immunity and adipose tissue biology[J].Trends Immunol, 2010, 31(6): 228-235.

[47]Mercedes Monteleone, Jennifer L Stow, Kate Schroder. Mechanisms of unconventional secretion of IL-1 family cytokines[J].Cytokine, 2015, 74(2): 213-218.

[48]Jean-Philippe Michaud, Serge Rivest. Anti-inflammatory signaling in microglia exacerbates Alzheimer's disease-related pathology[J].Neuron, 2015, 85(3): 450-452.

[49]Marie-Victoire Guillot-Sestier, Kevin R Doty, David Gate, et al. IL10 deficiency re-balances innate immunity to mitigate Alzheimer-like pathology[J].Neuron, 2015, 85(3): 5345-5348.

[50]Masato Mitsuhashi, Dennis D Taub, Dimitrios Kapogiannis, et al. Aging enhances release of exosomal cytokine mRNAs by Aβ1-42-stimulated macrophages[J].FASEB J, 2013, 27(12): 5141-5150.

[51] Cristiano Capurso. Has dysregulated interleukin-6 gene a role in the development of Alzheimer's disease? [J].Neurosci Lett, 2011, 504(1): 1-3.

[52]Moonhee Lee, Edith McGeer, Patrick L McGeer. Activated human microglia stimulate neuroblastoma cells to upregulate production of beta amyloid protein and tau: implications for Alzheimer's disease pathogenesis[J].Neurobiology Aging, 2015, 36(1): 42-52.

[53]Xie Lu-shuang, Lai Yu, Lei Fang, et al. Exploring the association between interleukin-1β and its interacting proteins in Alzheimer's disease[J].Mol Med Rep, 2015, 11(5): 3219-3228.

[54] Marco A Meraz-Ríos, Danira Toral-Rios, Diana Franco-Bocanegra, et al. Inflammatory process in Alzheimer's Disease [J].Front Integr Neurosci, 2013, 7(4):59.

[55] Federica Prati, Manuela Bartolini, Elena Simoni, et al. Quinones bearing non-steroidal anti-inflammatory fragments as multitarget ligands for Alzheimer's disease[J].Bioorg Med Chem Lett, 2013, 23(23): 6254-6258.

[56] Curat C A, Wegner V, Sengenes C, et al. Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin [J]. Diabetologia, 2006, 49(4): 744-747.

[57] Kanda N, Hau C S, Tada Y, et al. Visfatin enhances CXCL8, CXCL10, and CCL20 production in human keratinocytes [J]. Endocrinology, 2011, 152(8): 3155-3164.

[58] Li Yan-kun, Zhang Yuan, Bernhard Dorweiler, et al. Extracellular Nampt promotes macrophage survival via a nonenzymatic interleukin-6/STAT3 signaling mechanism[J].J Biol Chem, 2008, 283(50): 34833-34843.

[59]Ching-Wen Huang, Shang-Jang Wang, Shyh-Jong Wu, et al. Potential blood biomarker for disease severity in the taiwanese population with Alzheimer's disease[J].Am J Alzheimers Dis Other Demen, 2013, 28(1): 75-83.

脂肪因子参与阿尔茨海默病的研究进展

Progress on Adipokines Participating in Alzheimer’s Disease

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章15

编辑推荐

Metrics

[1]	谢彬, 黄志源, 林多朵, 杨福龙, 谢奕彬.针药结合干预阿尔茨海默病抑郁症状效果分析[J]. 神经药理学报, 2020, 10(5): 5-8.
[2]	赵雨薇, 甄艳杰, 戴月英, 沈丽霞.槲皮素对阿尔茨海默症神经保护作用研究[J]. 神经药理学报, 2020, 10(5): 55-64.
[3]	海吉涛, 罗焕敏.病原微生物与阿尔茨海默病相关性研究进展[J]. 神经药理学报, 2020, 10(4): 58-64.
[4]	杨旭华, 杜爽, 沈丽霞, 郝军荣.阿尔茨海默病的药物治疗研究进展[J]. 神经药理学报, 2020, 10(3): 47-53.
[5]	甄艳杰, 郭童林, 赵雨薇, 沈丽霞.植物雌激素介导线粒体途径对阿尔茨海默病神经保护作用的研究进展[J]. 神经药理学报, 2020, 10(1): 40-46.
[6]	杨琳，艾静.脑源雌激素在阿尔茨海默病中的作用研究进展[J]. 神经药理学报, 2019, 9(5): 50-64.
[7]	张帅，艾静.谷氨酸功能异常与阿尔茨海默病[J]. 神经药理学报, 2018, 8(6): 9-20.
[8]	SHEN li-xia1，LIU Liang-liang1，ZHANG Ming1，LIU Yang1，ZHANG Dan-shen 2*.Research of Quercetin’s Estrogen-Like Action on Central Nervous System and Its Mechanisms[J]. 神经药理学报, 2018, 8(4): 23-25.
[9]	黄蕊，杨翠翠，张兰.二苯乙烯苷对APP/PS1 双转基因小鼠学习记忆及突触可塑性的影响[J]. 神经药理学报, 2018, 8(2): 31-31.
[10]	雷曦，王健辉，程肖蕊，张小锐，刘港，周文霞，张永祥.基于快速老化模型小鼠SAMP8 的CA-30 抗阿尔茨海默病的作用研究[J]. 神经药理学报, 2018, 8(2): 50-50.
[11]	王健辉，程肖蕊，张小锐，刘港，周文霞，张永祥.药物组合吲哚美辛与阿托伐他汀对阿尔茨海默病的治疗作用研究[J]. 神经药理学报, 2018, 8(2): 52-52.
[12]	王静，程肖蕊，周文霞，张永祥.快速老化模型小鼠海马囊泡谷氨酸转运体表达与兴奋性毒性关系的研究[J]. 神经药理学报, 2018, 8(2): 53-53.
[13]	张林，蒋宁，周文霞，张永祥.疾病特异性诱导性多功能干细胞AD 模型建立[J]. 神经药理学报, 2018, 8(2): 54-54.
[14]	郭鹏，张巍.阿尔茨海默病患者睡眠障碍及其与认知障碍关系的研究[J]. 神经药理学报, 2018, 8(2): 61-61.
[15]	连腾宏，李少武，余秋瑾，等.阿尔茨海默病伴发嗅觉障碍的临床特点及静息态功能核磁共振成像的研究[J]. 神经药理学报, 2018, 8(2): 62-62.