APOE基因多态性在神经退行性疾病中的功能异质性及其机制探讨
Study on Functional Heterogeneity of APOE Gene Polymorphism in Neurodegenerative Diseases and Its Underlying Mechanisms
DOI: 10.12677/acm.2026.1662290, PDF,   
作者: 郭可云：成都中医药大学临床医学院，四川 成都；杨东东*：成都中医药大学附属医院神经内科，四川 成都
关键词: 载脂蛋白E；基因多态性；神经退行性疾病；功能异质性；Apolipoprotein E； Genetic Polymorphism； Neurodegenerative Diseases； Functional Heterogeneity
摘要: 载脂蛋白E (APOE)作为脂质转运和神经稳态的重要调节因子，在多种神经退行性疾病中发挥着重要作用。人类APOE基因主要存在三种等位基因亚型，分别为APOEε2、APOEε3、APOEε4，其中APOEε4被广泛认为是阿尔茨海默病、帕金森病、脑淀粉样血管病的重要遗传易感因素，APOEε4通过促进β-淀粉样蛋白与Tau蛋白的聚集沉积、扰乱神经系统的脂质代谢平衡、诱导神经炎症反应的持续激活，以及损害血脑屏障的完整性等方式推动疾病进程，进而导致神经元功能障碍。另一方面，APOEε2等位基因在帕金森病中展现出显著的神经保护潜能。基于APOE复杂的病理机制，目前多种靶向治疗策略正在积极探索，包括模拟肽干预、基因编辑、AAV介导基因递送、反义寡核苷酸抑制、免疫治疗及脂质化调控等。本文将围绕APOE的结构特点与生物学功能展开系统性综述，同时进一步从神经元、星形胶质细胞、小胶质细胞、少突胶质细胞及脑血管单元等细胞层面总结APOE作用网络，并归纳当前争议、关键科学问题与未来研究方向，以期深化对APOE功能异质性的机制认识，并为后续研究和精准干预提供参考。
Abstract: Apolipoprotein E (APOE), an important regulator of lipid transport and neural homeostasis, plays a critical role in multiple neurodegenerative diseases. The human APOE gene mainly includes three allelic isoforms, namely APOEε2, APOEε3, and APOEε4. Among them, APOEε4 is widely recognized as an important genetic susceptibility factor for Alzheimer’s disease, Parkinson’s disease, and cerebral amyloid angiopathy. APOEε4 promotes disease progression by facilitating the aggregation and deposition of β-amyloid and Tau proteins, disrupting lipid metabolic homeostasis in the nervous system, inducing sustained activation of neuroinflammatory responses, and impairing the integrity of the blood-brain barrier, ultimately leading to neuronal dysfunction. In contrast, the APOEε2 allele has shown notable neuroprotective potential in Parkinson’s disease. Given the complex pathological mechanisms of APOE, various APOE-targeted therapeutic strategies are currently being actively explored, including mimetic peptide intervention, gene editing, AAV-mediated gene delivery, antisense oligonucleotide suppression, immunotherapy, and lipidation regulation. This review systematically summarizes the structural characteristics and biological functions of APOE. Furthermore, it discusses the APOE-related regulatory network at the cellular level, including neurons, astrocytes, microglia, oligodendrocytes, and the neurovascular unit, and summarizes current controversies, key scientific questions, and future research directions. This review aims to deepen mechanistic understanding of APOE functional heterogeneity and provide references for future research and precision intervention.
文章引用：郭可云, 杨东东. APOE基因多态性在神经退行性疾病中的功能异质性及其机制探讨[J]. 临床医学进展, 2026, 16(6): 882-891. https://doi.org/10.12677/acm.2026.1662290

参考文献

[1] Patsch, W., Schonfeld, G., Gotto Jr., A.M. and Patsch, J.R. (1980) Characterization of Human High Density Lipoproteins by Zonal Ultracentrifugation. Journal of Biological Chemistry, 255, 3178-3185. [Google Scholar] [CrossRef] [PubMed]
[2] Utermann, G., Langenbeck, U., Beisiegel, U., et al. (1980) Genetics of the Apolipoprotein E System in Man. American Journal of Human Genetics, 32, 339-347.
[3] Huang, Y.A., Zhou, B., Wernig, M. and Südhof, T.C. (2017) ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and Aβ Secretion. Cell, 168, 427-441.E21. [Google Scholar] [CrossRef] [PubMed]
[4] Mahley, R.W. (2016) Apolipoprotein E: From Cardiovascular Disease to Neurodegenerative Disorders. Journal of Molecular Medicine, 94, 739-746. [Google Scholar] [CrossRef] [PubMed]
[5] Yamazaki, Y., Painter, M.M., Bu, G. and Kanekiyo, T. (2016) Apolipoprotein E as a Therapeutic Target in Alzheimer’s Disease: A Review of Basic Research and Clinical Evidence. CNS Drugs, 30, 773-789. [Google Scholar] [CrossRef] [PubMed]
[6] Huebbe, P. and Rimbach, G. (2017) Evolution of Human Apolipoprotein E (APOE) Isoforms: Gene Structure, Protein Function and Interaction with Dietary Factors. Ageing Research Reviews, 37, 146-161. [Google Scholar] [CrossRef] [PubMed]
[7] Martínez-Martínez, A.B., Torres-Perez, E., Devanney, N., Del Moral, R., Johnson, L.A. and Arbones-Mainar, J.M. (2020) Beyond the CNS: The Many Peripheral Roles of ApoE. Neurobiology of Disease, 138, Article 104809. [Google Scholar] [CrossRef] [PubMed]
[8] Gong, C., Song, W., Zhu, Z., Yang, D., Zhao, X., Xu, Y., et al. (2025) APOEε4 Influences the Dynamic Functional Connectivity Variability and Cognitive Performance in Alzheimer’s Disease. Journal of Alzheimer’s Disease, 104, 1103-1114.
[9] Li, Z., Shue, F., Zhao, N., Shinohara, M. and Bu, G. (2020) ApoE2: Protective Mechanism and Therapeutic Implications for Alzheimer’s Disease. Molecular Neurodegeneration, 15, Article No. 63. [Google Scholar] [CrossRef] [PubMed]
[10] Staurenghi, E., Leoni, V., Lo Iacono, M., Sottero, B., Testa, G., Giannelli, S., et al. (2022) ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis. Antioxidants, 11, Article 2168. [Google Scholar] [CrossRef] [PubMed]
[11] Qi, G., Mi, Y., Shi, X., Gu, H., Brinton, R.D. and Yin, F. (2021) ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism. Cell Reports, 34, Article 108572. [Google Scholar] [CrossRef] [PubMed]
[12] Spires-Jones, T.L. and Hyman, B.T. (2014) The Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease. Neuron, 82, 756-771. [Google Scholar] [CrossRef] [PubMed]
[13] Bloom, G.S. (2014) Amyloid-β and Tau: The Trigger and Bullet in Alzheimer Disease Pathogenesis. JAMA Neurology, 71, 505-508. [Google Scholar] [CrossRef] [PubMed]
[14] Foley, K.E. and Wilcock, D.M. (2024) Three Major Effects of APOEε4 on Aβ Immunotherapy Induced Aria. Frontiers in Aging Neuroscience, 16, Article 1412006. [Google Scholar] [CrossRef] [PubMed]
[15] Deane, R., Sagare, A., Hamm, K., Parisi, M., Lane, S., Finn, M.B., et al. (2008) ApoE Isoform-Specific Disruption of Amyloid β Peptide Clearance from Mouse Brain. Journal of Clinical Investigation, 118, 4002-4013. [Google Scholar] [CrossRef] [PubMed]
[16] Blanchard, J.W., Bula, M., Davila-Velderrain, J., Akay, L.A., Zhu, L., Frank, A., et al. (2020) Reconstruction of the Human Blood-Brain Barrier in Vitro Reveals a Pathogenic Mechanism of ApoE4 in Pericytes. Nature Medicine, 26, 952-963. [Google Scholar] [CrossRef] [PubMed]
[17] Theendakara, V., Bredesen, D.E. and Rao, R.V. (2017) Downregulation of Protein Phosphatase 2A by Apolipoprotein E: Implications for Alzheimer’s Disease. Molecular and Cellular Neuroscience, 83, 83-91. [Google Scholar] [CrossRef] [PubMed]
[18] Yin, Z., Rosenzweig, N., Kleemann, K.L., Zhang, X., Brandão, W., Margeta, M.A., et al. (2023) ApoE4 Impairs the Microglial Response in Alzheimer’s Disease by Inducing TGFβ-Mediated Checkpoints. Nature Immunology, 24, 1839-1853. [Google Scholar] [CrossRef] [PubMed]
[19] Calabresi, P., Mechelli, A., Natale, G., Volpicelli-Daley, L., Di Lazzaro, G. and Ghiglieri, V. (2023) Alpha-Synuclein in Parkinson’s Disease and Other Synucleinopathies: From Overt Neurodegeneration Back to Early Synaptic Dysfunction. Cell Death & Disease, 14, Article No. 176. [Google Scholar] [CrossRef] [PubMed]
[20] Ihse, E., Yamakado, H., van Wijk, X.M., Lawrence, R., Esko, J.D. and Masliah, E. (2017) Cellular Internalization of Alpha-Synuclein Aggregates by Cell Surface Heparan Sulfate Depends on Aggregate Conformation and Cell Type. Scientific Reports, 7, Article No. 9008. [Google Scholar] [CrossRef] [PubMed]
[21] Zhao, N., Attrebi, O.N., Ren, Y., Qiao, W., Sonustun, B., Martens, Y.A., et al. (2020) ApoE4 Exacerbates α-Synuclein Pathology and Related Toxicity Independent of Amyloid. Science Translational Medicine, 12, eaay1809. [Google Scholar] [CrossRef] [PubMed]
[22] Hauser, P.S., Narayanaswami, V. and Ryan, R.O. (2011) Apolipoprotein E: From Lipid Transport to Neurobiology. Progress in Lipid Research, 50, 62-74. [Google Scholar] [CrossRef] [PubMed]
[23] Wahrle, S.E., Jiang, H., Parsadanian, M., Legleiter, J., Han, X., Fryer, J.D., et al. (2004) ABCA1 Is Required for Normal Central Nervous System ApoE Levels and for Lipidation of Astrocyte-Secreted ApoE. Journal of Biological Chemistry, 279, 40987-40993. [Google Scholar] [CrossRef] [PubMed]
[24] Nguyen, D., Dhanasekaran, P., Nickel, M., Nakatani, R., Saito, H., Phillips, M.C., et al. (2010) Molecular Basis for the Differences in Lipid and Lipoprotein Binding Properties of Human Apolipoproteins E3 and E4. Biochemistry, 49, 10881-10889. [Google Scholar] [CrossRef] [PubMed]
[25] Lee, H., Cho, S., Kim, M., Park, Y.J., Cho, E., Jo, Y.S., et al. (2023) ApoE4-Dependent Lysosomal Cholesterol Accumulation Impairs Mitochondrial Homeostasis and Oxidative Phosphorylation in Human Astrocytes. Cell Reports, 42, Article 113183. [Google Scholar] [CrossRef] [PubMed]
[26] Haney, M.S., Pálovics, R., Munson, C.N., Long, C., Johansson, P.K., Yip, O., et al. (2024) APOE4/4 Is Linked to Damaging Lipid Droplets in Alzheimer’s Disease Microglia. Nature, 628, 154-161. [Google Scholar] [CrossRef] [PubMed]
[27] Yang, L.G., March, Z.M., Stephenson, R.A. and Narayan, P.S. (2023) Apolipoprotein E in Lipid Metabolism and Neurodegenerative Disease. Trends in Endocrinology & Metabolism, 34, 430-445. [Google Scholar] [CrossRef] [PubMed]
[28] Dias, D., Portugal, C.C., Relvas, J. and Socodato, R. (2025) From Genetics to Neuroinflammation: The Impact of ApoE4 on Microglial Function in Alzheimer’s Disease. Cells, 14, Article 243. [Google Scholar] [CrossRef] [PubMed]
[29] Jeong, W., Lee, H., Cho, S., et al. (2019) ApoE4-Induced Cholesterol Dysregulation and Its Brain Cell Type-Specific Implications in the Pathogenesis of Alzheimer’s Disease. Molecular Cells, 42, 739-746.
[30] Lee, S., Devanney, N.A., Golden, L.R., Smith, C.T., Schwartz, J.L., Walsh, A.E., et al. (2023) APOE Modulates Microglial Immunometabolism in Response to Age, Amyloid Pathology, and Inflammatory Challenge. Cell Reports, 42, Article 112196. [Google Scholar] [CrossRef] [PubMed]
[31] Szeto, J.Y.Y., Walton, C.C., Rizos, A., Martinez-Martin, P., Halliday, G.M., Naismith, S.L., et al. (2020) Dementia in Long-Term Parkinson’s Disease Patients: A Multicentre Retrospective Study. npj Parkinson’s Disease, 6, Article No. 2. [Google Scholar] [CrossRef] [PubMed]
[32] Huang, M., Wang, Y., Wang, L., Chen, B., Wang, X. and Hu, Y. (2020) APOE Rs405509 Polymorphism and Parkinson’s Disease Risk in the Chinese Population. Neuroscience Letters, 736, Article 135256. [Google Scholar] [CrossRef] [PubMed]
[33] Real, R., Martinez-Carrasco, A., Reynolds, R.H., Lawton, M.A., Tan, M.M.X., Shoai, M., et al. (2023) Association between the LRP1B and APOE Loci and the Development of Parkinson’s Disease Dementia. Brain, 146, 1873-1887. [Google Scholar] [CrossRef] [PubMed]
[34] Fu, Y., Zhao, J., Atagi, Y., Nielsen, H.M., Liu, C., Zheng, H., et al. (2016) Apolipoprotein E Lipoprotein Particles Inhibit Amyloid-β Uptake through Cell Surface Heparan Sulphate Proteoglycan. Molecular Neurodegeneration, 11, Article No. 37. [Google Scholar] [CrossRef] [PubMed]
[35] Huang, P., Zhang, Z., Zhang, P., Feng, J., Xie, J., Zheng, Y., et al. (2024) TREM2 Deficiency Aggravates NLRP3 Inflammasome Activation and Pyroptosis in MPTP-Induced Parkinson’s Disease Mice and LPS-Induced BV2 Cells. Molecular Neurobiology, 61, 2590-2605. [Google Scholar] [CrossRef] [PubMed]
[36] Krasemann, S., Madore, C., Cialic, R., Baufeld, C., Calcagno, N., El Fatimy, R., et al. (2017) The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity, 47, 566-581.E9. [Google Scholar] [CrossRef] [PubMed]
[37] Parhizkar, S. and Holtzman, D.M. (2022) APOE Mediated Neuroinflammation and Neurodegeneration in Alzheimer’s Disease. Seminars in Immunology, 59, Article 101594. [Google Scholar] [CrossRef] [PubMed]
[38] Saher, G., Quintes, S. and Nave, K. (2011) Cholesterol: A Novel Regulatory Role in Myelin Formation. The Neuroscientist, 17, 79-93. [Google Scholar] [CrossRef] [PubMed]
[39] Wuerch, E.C. and Yong, V.W. (2025) Cholesterol in the CNS: Functions, Recycling and Remyelination. Journal of Neuroinflammation, 22, Article No. 180. [Google Scholar] [CrossRef] [PubMed]
[40] Blanchard, J.W., Akay, L.A., Davila-Velderrain, J., von Maydell, D., Mathys, H., Davidson, S.M., et al. (2022) APOE4 Impairs Myelination via Cholesterol Dysregulation in Oligodendrocytes. Nature, 611, 769-779. [Google Scholar] [CrossRef] [PubMed]
[41] McConnell, H.L. and Mishra, A. (2022) Cells of the Blood-Brain Barrier: An Overview of the Neurovascular Unit in Health and Disease. In: Stone, N., Ed., Methods in Molecular Biology, Springer, 3-24. [Google Scholar] [CrossRef] [PubMed]
[42] Wang, N., Yang, X., Zhao, Z., Liu, D., Wang, X., Tang, H., et al. (2023) Cooperation between Neurovascular Dysfunction and Aβ in Alzheimer’s Disease. Frontiers in Molecular Neuroscience, 16, Article 1227493. [Google Scholar] [CrossRef] [PubMed]
[43] Storck, S.E., Meister, S., Nahrath, J., Meißner, J.N., Schubert, N., Di Spiezio, A., et al. (2016) Endothelial LRP1 Transports Amyloid-β1-42 across the Blood-Brain Barrier. Journal of Clinical Investigation, 126, 123-136. [Google Scholar] [CrossRef] [PubMed]
[44] Gowdy, J., Ahn, J., Miller, R.H. and Islam, Y. (2026) Neurovascular Dysfunction in the Development and Progression of Neuroinflammatory Diseases. Frontiers in Cellular Neuroscience, 20, Article 1741928. [Google Scholar] [CrossRef] 
[45] Duka, T., Duka, V., Joyce, J.N. and Sidhu, A. (2009) α-Synuclein Contributes to Gsk-3β-Catalyzed Tau Phosphorylation in Parkinson’s Disease Models. The FASEB Journal, 23, 2820-2830. [Google Scholar] [CrossRef] [PubMed]
[46] Insel, P.S., Hansson, O. and Mattsson-Carlgren, N. (2021) Association between Apolipoprotein E ε2 vs ε4, Age, and β-Amyloid in Adults without Cognitive Impairment. JAMA Neurology, 78, 229-235. [Google Scholar] [CrossRef] [PubMed]
[47] Li, Y., Xia, Y., Yin, S., Wan, F., Hu, J., Kou, L., et al. (2021) Targeting Microglial α-Synuclein/TLRs/NF-KAPPAB/NLRP3 Inflammasome Axis in Parkinson’s Disease. Frontiers in Immunology, 12, Article 719807. [Google Scholar] [CrossRef] [PubMed]
[48] Szidonya, L. and Nickerson, J.P. (2023) Cerebral Amyloid Angiopathy. Radiologic Clinics of North America, 61, 551-562. [Google Scholar] [CrossRef] [PubMed]
[49] Hu, H., Wan, S., Hu, Y., Wang, Q., Li, H. and Zhang, N. (2025) Deciphering the Role of APOE in Cerebral Amyloid Angiopathy: From Genetic Insights to Therapeutic Horizons. Annals of Medicine, 57, Article 2445194. [Google Scholar] [CrossRef] [PubMed]
[50] Montagne, A., Nikolakopoulou, A.M., Huuskonen, M.T., Sagare, A.P., Lawson, E.J., Lazic, D., et al. (2021) APOE4 Accelerates Advanced-Stage Vascular and Neurodegenerative Disorder in Old Alzheimer’s Mice via Cyclophilin A Independently of Amyloid-β. Nature Aging, 1, 506-520. [Google Scholar] [CrossRef] [PubMed]
[51] Zhang, L., He, S., Li, Z., Gan, X., Li, S., Cheng, X., et al. (2019) Apolipoprotein E Polymorphisms Contribute to Statin Response in Chinese ASCVD Patients with Dyslipidemia. Lipids in Health and Disease, 18, Article No. 129. [Google Scholar] [CrossRef] [PubMed]
[52] Croy, J.E., Brandon, T. and Komives, E.A. (2004) Two Apolipoprotein E Mimetic Peptides, ApoE(130-149) and ApoE(141-155)2, Bind to LRP1. Biochemistry, 43, 7328-7335. [Google Scholar] [CrossRef] [PubMed]
[53] Xu, Y., Liu, H., Liu, M., et al. (2016) A Human Apolipoprotein E Mimetic Peptide Reduces Atherosclerosis in Aged Apolipoprotein E Null Mice. American Journal of Translational Research, 8, 3482-3492.
[54] Lanfranco, M.F., Ng, C.A. and Rebeck, G.W. (2020) APOE Lipidation as a Therapeutic Target in Alzheimer’s Disease. International Journal of Molecular Sciences, 21, Article 6336. [Google Scholar] [CrossRef] [PubMed]
[55] Mahley, R.W. and Huang, Y. (2012) Small-Molecule Structure Correctors Target Abnormal Protein Structure and Function: Structure Corrector Rescue of Apolipoprotein E4-Associated Neuropathology. Journal of Medicinal Chemistry, 55, 8997-9008. [Google Scholar] [CrossRef] [PubMed]
[56] Li, A., Cartwright, S., Yu, A., Ho, S., Schrode, N., Deans, P.J.M., et al. (2021) Using the dCas9-KRAB System to Repress Gene Expression in hiPSC-Derived NGN2 Neurons. STAR Protocols, 2, Article 100580. [Google Scholar] [CrossRef] [PubMed]
[57] Johnson, K.G., Kaplitt, M., Kaminsky, S., Sondhi, D., Amato, G., Selvan, N., et al. (2025) Topline Results from Phase 1/2 AAV Gene Therapy (LX1001) in APOE4/4 Homozygotes with Alzheimer’s Disease. Alzheimer’s & Dementia, 21, e101538. [Google Scholar] [CrossRef] 
[58] Wang, J., Gessler, D.J., Zhan, W., Gallagher, T.L. and Gao, G. (2024) Adeno-Associated Virus as a Delivery Vector for Gene Therapy of Human Diseases. Signal Transduction and Targeted Therapy, 9, Article No. 78. [Google Scholar] [CrossRef] [PubMed]
[59] Liao, F., Li, A., Xiong, M., Bien-Ly, N., Jiang, H., Zhang, Y., et al. (2018) Targeting of Nonlipidated, Aggregated ApoE with Antibodies Inhibits Amyloid Accumulation. Journal of Clinical Investigation, 128, 2144-2155. [Google Scholar] [CrossRef] [PubMed]
[60] Litvinchuk, A., Huynh, T.V., Shi, Y., Jackson, R.J., Finn, M.B., Manis, M., et al. (2021) Apolipoprotein E4 Reduction with Antisense Oligonucleotides Decreases Neurodegeneration in a Tauopathy Model. Annals of Neurology, 89, 952-966. [Google Scholar] [CrossRef] [PubMed]
[61] Wahrle, S.E., Jiang, H., Parsadanian, M., Kim, J., Li, A., Knoten, A., et al. (2008) Overexpression of ABCA1 Reduces Amyloid Deposition in the PDAPP Mouse Model of Alzheimer Disease. Journal of Clinical Investigation, 118, 671-682. [Google Scholar] [CrossRef] [PubMed]
[62] Boehm-Cagan, A. and Michaelson, D.M. (2014) Reversal of ApoE4-Driven Brain Pathology and Behavioral Deficits by Bexarotene. The Journal of Neuroscience, 34, 7293-7301. [Google Scholar] [CrossRef] [PubMed]

为你推荐