APOE基因型多态性对阿尔茨海默病应激过程的影响
Effect of APOE Genotype Polymorphism on Stress in Alzheimer’s Disease
DOI: 10.12677/IJPN.2017.63010, PDF, HTML, XML, 下载: 1,812  浏览: 4,673 
作者: 乔向向:青海大学医学院,青海 西宁;朱爱琴:青海省人民医院,青海 西宁
关键词: 阿尔茨海默病载脂蛋白E基因氧化应激内质网应激线粒体功能Alzheimer’s Disease Apolipoprotein E Gene Oxidative Stress Endoplasmic Reticulum Stress Mitochondrial Function
摘要: 目前仅有两个基因与长寿密切相关,APOE就是其中之一。载脂蛋白E(APOE)是一种在脂质和脂蛋白代谢中起重要作用的血浆蛋白。在人类有三种主要的APOE亚型,为APOE2,APOE3和APOE4。在这三种亚型中,APOE3是最常见的,而APOE4显示与年龄相关的疾病(包括心血管和阿尔茨海默病)相关,并随着年龄的增加导致死亡风险增加。APOE 基因多态性影响氧化应激和相应的线粒体功能。APOE 基因多态性参与衰老过程的应激反应,包括内质网应激反应和免疫功能。本文阐述APOE基因型对应激反应过程的影响,着重介绍线粒体功能,内质网应激和免疫反应之间的关系。
Abstract: Currently, only two genes are closely related to longevity, and APOE is one of them. Apolipoprotein E (APOE) is a plasma protein that plays an important role in the metabolism of lipids and lipoproteins. In humans, there are three major APOE subtypes, APOE2, APOE3, and APOE4. Of these three subtypes, APOE3 is the most common, while APOE4 appears to be associated with age related diseases, including cardiovascular and Alzheimer’s disease, and is associated with an increased risk of death as age increases. The APOE polymorphism affects oxidative stress and the corresponding mitochondrial function. The APOE gene polymorphism is involved in the stress response of the aging process, including endoplasmic reticulum stress and immune function. This review describes the effects of APOE genotype on stress response, focusing on the relationship between mitochondrial function, endoplasmic reticulum stress and immune response.
文章引用:乔向向, 朱爱琴. APOE基因型多态性对阿尔茨海默病应激过程的影响[J]. 国际神经精神科学杂志, 2017, 6(3): 56-64. https://doi.org/10.12677/IJPN.2017.63010

参考文献

[1] Alzheimer’s Disease International Consortium. World Alzheimer Report 2015. http://www.alz.co.uk/research/WorldAlzheimerReport2015.pdf
[2] Blennow, K., de Leon, M.J. and Zetterberg, H. (2006) Alzheimer’s Disease. Lancet, 368, 387-403.
https://doi.org/10.1016/S0140-6736(06)69113-7
[3] Gatz, M., Reynolds, C.A., Fratiglioni, L., et al. (2006) Role of Genes and Environments for Explaining Alzheimer Disease. Archives of General Psychiatry, 63, 168-174.
https://doi.org/10.1001/archpsyc.63.2.168
[4] Liu, C.C., Kanekiyo, T., Xu, H. and Bu, G. (2013) Apolipoprotein E and Alzheimer Disease: Risk, Mechanisms and Therapy. Nature Reviews Neurology, 9, 106-118.
https://doi.org/10.1038/nrneurol.2012.263
[5] Gispert, J.D., Rami, L., Sanchez-Benavides, G., Falcon, C., Tucholka, A., Rojas, S., et al. (2015) Nonlinear Cerebral Atrophy Patterns across the Alzheimer’s Disease Continuum: Impact of APOE4 Genotype. Neurobiology of Aging, 36, 2687-2701.
https://doi.org/10.1016/j.neurobiolaging.2015.06.027
[6] Liu, Y., Yu, J.T., Wang, H.F., Han, P.R., Tan, C.C., Wang, C., et al. (2015) APOE Genotype and Neuroimaging Markers of Alzheimer’s Disease: Systematic Review and Meta-Analysis. Journal of Neurology, Neurosurgery, & Psychiatry, 86, 127-134.
https://doi.org/10.1136/jnnp-2014-307719
[7] Kim, J., Basak, J.M. and Holtzman, D.M. (2009) The Role of Apolipoprotein E in Alzheimer’s Disease. Neuron, 63, 287-303.
https://doi.org/10.1016/j.neuron.2009.06.026
[8] Heneka, M.T., Carson, M.J., El Khoury, J., Landreth, G.E., Brosseron, F., Feinstein, D.L., et al. (2015) Neuroinflammation in Alzheimer’s Disease. The Lancet Neurology, 14, 388-405.
https://doi.org/10.1016/S1474-4422(15)70016-5
[9] Atagi, Y., Liu, C.C., Painter, M.M., Chen, X.F., Verbeeck, C., Zheng, H., et al. (2015) Apo Poprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2). The Journal of Biological Chemistry, 290, 26043-26050.
https://doi.org/10.1074/jbc.M115.679043
[10] Getz, G.S. and Reardon, C.A. (2009) Apoprotein E as a Lipid Transport and Signaling Protein in the Blood, Liver, and Artery Wall. The Journal of Lipid Research, 50, S156-S161.
https://doi.org/10.1194/jlr.R800058-JLR200
[11] Ang, L.S., Cruz, R.P., Hendel, A. and Granville, D.J. (2008) Apolipoprotein E, an Important Player in Longevity and Age-Related Diseases. Experimental Gerontology, 43, 615-622.
[12] Matsuura, F., Wang, N., Chen, W., Jiang, X.C. and Tall, A.R. (2006) HDL from CETP-Deficient Subjects Shows Enhanced Ability to Promote Cholesterol Efflux from Macrophages in an apoE- and ABCG1-Dependent Pathway. Journal of Clinical Investigation, 116, 1435-1442.
https://doi.org/10.1172/JCI27602
[13] Zanotti, I., Pedrelli, M., Pot, F., Stomeo, G., Gomaraschi, M., Calabresi, L. and Bernini, F. (2011) Macrophage, but Not Systemic, Apolipoprotein E Is Necessary for Macrophage Reverse Cholesterol Transport in Vivo. Arteriosclerosis, Thrombosis, and Vascular Biology, 31, 74-80.
https://doi.org/10.1161/ATVBAHA.110.213892
[14] Eichner, J.E., Dunn, S.T., Perveen, G., Thompson, D.M., Stewart, K.E. and Stroehla, B.C. (2002) Apolipoprotein E Polymorphism and Cardiovascular Disease: A Huge Review. American Journal of Epidemiology, 155, 487-495.
https://doi.org/10.1093/aje/155.6.487
[15] Van Oosten, M., Rensen, P.C.N., Van Amersfoort, E.S., Van Eck, M., Van Dam, A.-M., Brev, J.J.P., Vogel, T., Panet, A., Van Berkel, T.J.C. and Kuiper, J. (2001) Apolipoprotein E Protects against Bacterial Lipopolysaccharide-Induced Lethality. A New Therapeutic Approach to Treat Gram-Negative Sepsis. The Journal of Biological Chemistry, 276, 8820-8824.
https://doi.org/10.1074/jbc.M009915200
[16] Ikeno, Y. (2015) New Insights and Current Concepts of the Oxidative Stress Theory of Aging. Archives of Biochemistry and Biophysics, 576, 1.
[17] Tarnus, E., Wassef, H., Carmel, J.F., Rondeau, P., Roche, M., Davignon, J., Bernier, L. and Bourdon, E. (2009) Apolipoprotein E Limits Oxidative Stress-Induced Cell Dysfunctions in Human Adipocytes. FEBS Letters, 583, 2042-2048.
[18] Papaioannou, I., Simons, J.P. and Owen, J.S. (2012) Targeted in Situ Gene Correction of Dysfunctional APOE Alleles to Produce Atheroprotective Plasma ApoE3 Protein. Cardiology Research and Practice, 2012, Article ID: 148796.
https://doi.org/10.1155/2012/148796
[19] Lee, Y., Kockx, M., Raftery, M.J., Jessup, W., Griffith, R. and Kritharides, L. (2010) Glycosylation and Sialylation of Macrophage-Derived Human Apolipoprotein E Analyzed by SDS-PAGE and Mass Spectrometry: Evidence for a Novel Site of Glycosylation on Ser290. Molecular & Cellular Proteomics, 9, 1968-1981.
https://doi.org/10.1074/mcp.M900430-MCP200
[20] Singh, P.P., Singh, M. and Mastana, S.S. (2006) APOE Distribution in World Populations with New Data from India and the UK. Annals of Human Biology, 33, 279-308.
https://doi.org/10.1080/03014460600594513
[21] Frieden, C. and Garai, K. (2012) Structural Differences between apoE3 and apoE4 May Be Useful in Developing Therapeutic Agents for Alzheimer’s Disease. Proceedings of the National Academy of Sciences, 109, 8913-8918.
https://doi.org/10.1073/pnas.1207022109
[22] Dong, L.M., Wilson, C., Wardell, M.R., Simmons, T., Mahley, R.W., Weisgraber, K.H. and Agard, D.A. (1994) Human Apolipoprotein E. Role of Arginine 61 in Mediating the Lipoprotein Preferences of the E3 and E4 Isoforms. The Journal of Biological Chemistry, 269, 22358-22365.
[23] Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Small, G.W., Roses, A.D., Haines, J.L. and Pericak-Vance, M.A. (1993) Gene Dose of Apolipoprotein E Type 4 Allele and the Risk of Alzheimer’s Disease in Late Onset Families. Science, 261, 921-923.
https://doi.org/10.1126/science.8346443
[24] Miyata, M. and Smith, J.D. (1996) Apolipoprotein E Allele-Specific Antioxidant Activity and Effects on Cytotoxicity by Oxidative Insults and Beta-Amyloid Peptides. Nature Genetics, 14, 55-61.
https://doi.org/10.1038/ng0996-55
[25] Jofre-Monseny, L., Minihane, A.M. and Rimbach, G. (2008) Impact of apoE Genotype on Oxidative Stress, Inflammation and Disease Risk. Molecular Nutrition & Food Research, 52, 131-145.
https://doi.org/10.1002/mnfr.200700322
[26] Pocernich, C.B., Sultana, R., Hone, E., Turchan, J., Martins, R.N., Calabrese, V., Nath, A. and Butterfield, D.A. (2004) Effects of Apolipoprotein E on the Human Immunodeficiency Virus Protein Tat in Neuronal Cultures and Synaptosomes. Journal of Neuroscience Research, 77, 532-539.
https://doi.org/10.1002/jnr.20182
[27] Jofre-Monseny, L., de Pascual-Teresa, S., Plonka, E., Huebbe, P., Boesch-Saadatmandi, C., Minihane, A.M. and Rimbach, G. (2007) Differential Effects of Apolipoprotein E3 and E4 on Markers of Oxidative Status in Macrophages. British Journal of Nutrition, 97, 864-871.
https://doi.org/10.1017/S0007114507669219
[28] Jofre-Monseny, L., Huebbe, P., Stange, I., Boesch-Saadatmandi, C., Frank, J., Jackson, K., Minihane, A.-M. and Rimbach, G. (2008) Influence of Apolipoprotein E Genotype and Dietary Alpha-Tocopherol on Redox Status and C-Reactive Protein Levels in Apolipoprotein E3 and E4 Targeted Replacement Mice. British Journal of Nutrition, 100, 44-53.
https://doi.org/10.1017/S000711450788634X
[29] Talmud, P.J., Stephens, J.W., Hawe, E., Demissie, S., Cupples, L.A., Hurel, S.J., Humphries, S.E. and Ordovas, J.M. (2005) The Significant Increase in Cardiovascular Disease Risk in APOE 4 Carriers Is Evident Only in Men Who Smoke: Potential Relationship between Reduced Antioxidant Status and ApoE4. Annals of Human Genetics, 69, 613-622.
https://doi.org/10.1111/j.1529-8817.2005.00205.x
[30] Holmes, M.V., Frikke-Schmidt, R., Melis, D., Luben, R., Asselbergs, F.W., Boer, J.M.A., Cooper, J., Palmen, J., Horvat, P., Engmann, J., Li, K.W., Onland-Moret, N.C., Hofker, M.H., Kumari, M., Keating, B.J., Hubacek, J.A., Adamkova, V., Kubinova, R., Bobak, M., Khaw, K.T., Nordestgaard, B.G., Wareham, N., Humphries, S.E., Langenberg, C., Tybjaerg-Hansen, A. and Talmud, P.J. (2014) A Systematic Review and Meta-Analysis of 130,000 Individuals Shows Smoking Does Not Modify the Association of APOE Genotype on Risk of Coronary Heart Disease. Atherosclerosis, 237, 5-12.
[31] Ramassamy, C., Averill, D., Beffert, U., Theroux, L., Lussier-Cacan, S., Cohn, J.S., Christen, Y., Schoofs, A., Davignon, J. and Poirier, J. (2000) Oxidative Insults Are Associated with Apolipoprotein E Genotype in Alzheimer’s Disease Brain. Neurobiology of Disease, 7, 23-37.
https://doi.org/10.1006/nbdi.1999.0273
[32] Graeser, A.C., Huebbe, P., Storm, N., Höppner, W., Döring, F., Wagner, A.E. and Rimbach, G. (2012) Apolipoprotein E Genotype Affects Tissue Metallothionein Levels: Studies in Targeted Gene Replacement Mice. Genes & Nutrition, 7, 247-255.
https://doi.org/10.1007/s12263-012-0282-x
[33] Boesch-Saadatmandi, C., Niering, J., Minihane, A.M., Wiswedel, I., Gardeman, A., Wolffram, S. and Rimbach, G. (2010) Impact of Apolipoprotein E Genotype and Dietary Quercetin on Paraoxonase 1 Status in apoE3 and apoE4 Transgenic Mice. Atherosclerosis, 211, 110-113.
[34] Gaidukov, L., Viji, R.I., Yacobson, S., Rosenblat, M., Aviram, M. and Tawfik, D.S. (2010) ApoE Induces Serum Paraoxonase PON1 Activity and Stability Similar to ApoA-I. Biochemistry, 49, 532-538.
https://doi.org/10.1021/bi9013227
[35] Ross, J.M., Olson, L. and Coppotelli, G. (2015) Mitochondrial and Ubiquitin Proteasome System Dysfunction in Ageing and Disease: Two Sides of the Same Coin? International Journal of Molecular Sciences, 16, 19458-19476.
https://doi.org/10.3390/ijms160819458
[36] Bravo, R., Gutierrez, T., Paredes, F., Gatica, D., Rodriguez, A.E., Pedrozo, Z., Chiong, M., Parra, V., Quest, A.F.G., Rothermel, B.A. and Lavandero, S. (2012) Endoplasmic Reticulum: ER Stress Regulates Mitochondrial Bioenergetics. The International Journal of Biochemistry & Cell Biology, 44, 16-20.
[37] Brewer, J.W. (2014) Regulatory Crosstalk within the Mammalian Unfolded Protein Response. Cellular and Molecular Life Sciences, 71, 1067-1079.
https://doi.org/10.1007/s00018-013-1490-2
[38] Cao, S.S. and Kaufman, R.J. (2014) Endoplasmic Reticulum Stress and Oxidative Stress in Cell Fate Decision and Human Disease. Antioxidants & Redox Signaling, 21, 396-413.
https://doi.org/10.1089/ars.2014.5851
[39] Zhong, N., Ramaswamy, G. and Weisgraber, K.H. (2009) Apolipoprotein E4 Domain Interaction Induces Endoplasmic Reticulum Stress and Impairs Astrocyte Function. The Journal of Biological Chemistry, 284, 27273-27280.
https://doi.org/10.1074/jbc.M109.014464
[40] Zhong, N., Ramaswamy, G., Weisgraber, K.H. (2009) Apolipoprotein E4 Domain Interaction Induces Endoplasmic Reticulum Stress and Impairs Astrocyte Function. The Journal of Biological Chemistry, 284, 27273-27280.
[41] Brodbeck, J., McGuire, J., Liu, Z., Meyer-Franke, A., Balestra, M.E., Jeong, D.E., Pleiss, M., McComas, C., Hess, F., Witter, D., Peterson, S., Childers, M., Goulet, M., Liverton, N., Hargreaves, R., Freedman, S., Weisgraber, K.H., Mahley, R.W. and Huang, Y. (2011) Structure-Dependent Impairment of Intracellular Apolipoprotein E4 Trafficking and Its Detrimental Effects Are Rescued by Small-Molecule Structure Correctors. The Journal of Biological Chemistry, 286, 17217-17226.
https://doi.org/10.1074/jbc.M110.217380
[42] Segev, Y., Michaelson, D.M. and Rosenblum, K. (2013) ApoE 4 Is Associated with eIF2 Phosphorylation and Impaired Learning in Young Mice. Neurobiology of Aging, 34, 863-872.
[43] Eberl, D., Kim, R.Y., Luk, F.S., De Mochel, N.S.R., Gaudreault, N., Olivas, V.R., Kumar, N., Posada, J.M., Birkeland, A.C., Rapp, J.H. and Raffai, R.L. (2012) Apolipoprotein E4 Domain Interaction Accelerates Diet-Induced Atherosclerosis in Hypomorphic Arg-61 Apoe Mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 32, 1116-1123.
https://doi.org/10.1161/ATVBAHA.112.246389
[44] Sabaretnam, T., Harris, J.M., Kockx, M., Witting, P.K., Le Couteur, D.G. and Kritharides, L. (2009) Effects of Hydrogen Peroxide and Apolipoprotein E Isoforms on Apolipoprotein E Trafficking in HepG2 Cells. Clinical and Experimental Pharmacology and Physiology, 36, 96-102.
https://doi.org/10.1111/j.1440-1681.2009.05306.x
[45] Simpson, J.E., Ince, P.G., Shaw, P.J., Heath, P.R., Raman, R., Garwood, C.J., Gelsthorpe, C., Baxter, L., Forster, G., Matthews, F.E., Brayne, C. and Wharton, S.B. (2011) Microarray Analysis of the Astrocyte Transcriptome in the Aging Brain: Relationship to Alzheimer’s Pathology and APOE Genotype. Neurobiology of Aging, 32, 1795-1807.
[46] Nunnari, J. and Suomalainen, A. (2012) Mitochondria: In Sickness and in Health. Cell, 148, 1145-1159.
[47] Lopez-Mejia, I.C. and Fajas, L. (2015) Cell Cycle Regulation of Mitochondrial Function. Current Opinion in Cell Biology, 33, 19-25.
[48] Chen, H.K., Ji, Z.S., Dodson, S.E., Miranda, R.D., Rosenblum, C.I., Reynolds, I.J., Freedman, S.B., Weisgraber, K.H., Huang, Y. and Mahley, R.W. (2011) Apolipoprotein E4 Domain Interaction Mediates Detrimental Effects on Mitochondria and Is a Potential Therapeutic Target for Alzheimer Disease. The Journal of Biological Chemistry, 286, 5215-5221.
https://doi.org/10.1074/jbc.M110.151084
[49] Mosconi, L., Nacmias, B., Sorbi, S., De Cristofaro, M.T.R., Fayazz, M., Tedde, A., Bracco, L., Herholz, K. and Pupi, A. (2004) Brain Metabolic Decreases Related to the Dose of the ApoE e4 Allele in Alzheimer’s Disease. Journal of Neurology, Neurosurgery, & Psychiatry, 75, 370-376.
https://doi.org/10.1136/jnnp.2003.014993
[50] Mosconi, L., Herholz, K., Prohovnik, I., Nacmias, B., De Cristofaro, M.T.R., Fayyaz, M., Bracco, L., Sorbi, S. and Pupi, A. (2005) Metabolic Interaction between ApoE Genotype and Onset Age in Alzheimer’s Disease: Implications for Brain Reserve. Journal of Neurology, Neurosurgery, & Psychiatry, 76, 15-23.
https://doi.org/10.1136/jnnp.2003.030882
[51] Tamboli, I.Y., Heo, D. and Rebeck, G.W. (2014) Extracellular Proteolysis of Apolipoprotein E (apoE) by Secreted Serine Neuronal Protease. PLoS ONE, 9, e93120.
https://doi.org/10.1371/journal.pone.0093120
[52] Xu, H., Gupta, V.B., Martins, I.J., Martins, R.N., Fowler, C.J., Bush, A.I., Finkelstein, D.I. and Adlard, P.A. (2015) Zinc Affects the Proteolytic Stability of Apolipoprotein E in an Isoform-Dependent Way. Neurobiology of Disease, 81, 38-48.
[53] Nakamura, T., Watanabe, A., Fujino, T., Hosono, T. and Michikawa, M. (2009) Apolipoprotein E4 (1-272) Fragment Is Associated with Mitochondrial Proteins and Affects Mitochondrial Function in Neuronal Cells. Molecular Neurodegeneration, 4, 35.
https://doi.org/10.1186/1750-1326-4-35
[54] Chin, D., Hagl, S., Hoehn, A., Huebbe, P., Pallauf, K., Grune, T., Frank, J., Eckert, G.P. and Rimbach, G. (2014) Adenosine Triphosphate Concentrations Are Higher in the Brain of APOE3-Compared to APOE4-Targeted Replacement Mice and Can Be Modulated by Curcumin. Genes & Nutrition, 9, 397.
https://doi.org/10.1007/s12263-014-0397-3
[55] Su, B., Wang, X., Bonda, D., Perry, G., Smith, M. and Zhu, X. (2010) Abnormal Mitochondrial Dynamics—A Novel Therapeutic Target for Alzheimer’s Disease? Molecular Neurobiology, 41, 87-96.
https://doi.org/10.1007/s12035-009-8095-7
[56] Yu, C.E., Seltman, H., Peskind, E.R., Galloway, N., Zhou, P.X., Rosenthal, E., Wijsman, E.M., Tsuang, D.W., Devlin, B. and Schellenberg, G.D. (2007) Comprehensive Analysis of APOE and Selected Proximate Markers for Late-Onset Alzheimer’s Disease: Patterns of Linkage Disequilibrium and Disease/Marker Association. Genomics, 89, 655-665.
[57] Chaudhari, N., Talwar, P., Parimisetty, A., Lefebvre d’Hellencourt, C. and Ravanan, P. (2014) A Molecular Web: Endoplasmic Reticulum Stress, Inflammation and Oxidative Stress. Frontiers in Cellular Neuroscience, 8, 213.
https://doi.org/10.3389/fncel.2014.00213
[58] Zhang, H., Wu, L.M. and Wu, J. (2011) Cross-Talk between Apolipoprotein e and Cytokines. Mediators of Inflammation, 2011, Article ID: 949072.
https://doi.org/10.1155/2011/949072
[59] Li, X., Montine, K.S., Keene, C.D. and Montine, T.J. (2015) Different Mechanisms of Apolipoprotein E Isoform-Dependent Modulation of Prostaglandin E2 Production and Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Expression after Innate Immune Activation of Microglia. The FASEB Journal, 29, 1754-1762.
https://doi.org/10.1096/fj.14-262683
[60] Vitek, M.P., Brown, C.M. and Colton, C.A. (2009) APOE Genotype-Specific Differences in the Innate Immune Response. Neurobiology of Aging, 30, 1350-1360.