Tau蛋白在阿尔茨海默病中的发病机制及治疗策略进展
Advances in the Pathogenesis and Therapetic Strategies of Tau Proteins in Alzheimer’s Disease
DOI: 10.12677/pi.2025.142016, PDF,   
作者: 郑晴晴, 刘 煜*:中国药科大学生命科学与技术学院,江苏 南京
关键词: 阿尔茨海默病Tau蛋白发病机制治疗策略Alzheimer’s Disease Tau Protein Pathogenesis Treatment Strategy
摘要: 阿尔茨海默病(Alzheimer disease; AD)是一种慢性神经退行性疾病,以脑部变化为特征,导致记忆力、思维能力、行为和社会技能持续下降,最终影响患者的自理能力,主要发病机制由β-淀粉样蛋白(amyloid β-protein; Aβ)和Tau蛋白聚集沉积及两者相互作用所导致。Tau蛋白是一种微管相关蛋白,有助于神经元内部稳定,但病理性Tau蛋白会引起包括阿尔茨海默病在内的神经系统疾病,而且发现Tau蛋白与阿尔茨海默病患者认知水平存在正相关性。本文旨在讨论Tau蛋白在AD患者中的发病机制,以及靶向Tau的阿尔茨海默病的最新治疗策略。
Abstract: Alzheimer’s disease is a chronic neurodegenerative disorder characterized by brain changes that lead to a continuous decline in memory, thinking ability, behavior, and social skills, ultimately affecting the patient’s ability to take care of themselves. The main pathogenic mechanisms are caused by the aggregation and deposition of amyloid β-protein, Tau proteins, and the Aβ and Tau protein aggregation and deposition and their interaction. Tau protein is a microtubule-associated protein that contributes to internal stabilization of neurons. However, pathological Tau protein can cause neurological disorders, including Alzheimer’s disease, and it has been found that there is a positive correlation between Tau protein and the cognitive level of Alzheimer’s disease patients. This article aims to discuss the pathogenic mechanisms of Tau protein in Alzheimer’s disease patients and the latest treatment strategies for Alzheimer’s disease targeting Tau.
文章引用:郑晴晴, 刘煜. Tau蛋白在阿尔茨海默病中的发病机制及治疗策略进展[J]. 药物资讯, 2025, 14(2): 129-138. https://doi.org/10.12677/pi.2025.142016

参考文献

[1] 杨慧青. 如何预防和护理阿尔茨海默病[J]. 科学之友, 2024(12): 66-67.
[2] Jia, L., Du, Y., Chu, L., Zhang, Z., Li, F., Lyu, D., et al. (2020) Prevalence, Risk Factors, and Management of Dementia and Mild Cognitive Impairment in Adults Aged 60 Years or Older in China: A Cross-Sectional Study. The Lancet Public Health, 5, e661-e671. [Google Scholar] [CrossRef] [PubMed]
[3] Jia, J., Wei, C., Chen, S., Li, F., Tang, Y., Qin, W., et al. (2018) The Cost of Alzheimer’s Disease in China and Re‐estimation of Costs Worldwide. Alzheimer’s & Dementia, 14, 483-491. [Google Scholar] [CrossRef] [PubMed]
[4] 康馨谣, 许梅花, 董海静. 阿尔茨海默病发病机制的研究进展[J]. 中国老年学杂志, 2024, 44(22): 5625-5628.
[5] Goedert, M., Eisenberg, D.S. and Crowther, R.A. (2017) Propagation of Tau Aggregates and Neurodegeneration. Annual Review of Neuroscience, 40, 189-210. [Google Scholar] [CrossRef] [PubMed]
[6] Wang, Y. and Mandelkow, E. (2015) Tau in Physiology and Pathology. Nature Reviews Neuroscience, 17, 22-35. [Google Scholar] [CrossRef] [PubMed]
[7] Yang, J., Zhi, W. and Wang, L. (2024) Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review. Molecules, 29, Article 2812. [Google Scholar] [CrossRef] [PubMed]
[8] Zhu, L. and Qian, Z. (2022) Recent Studies of Atomic‐Resolution Structures of Tau Protein and Structure‐Based Inhibitors. Quantitative Biology, 10, 17-34. [Google Scholar] [CrossRef
[9] Neve, R.L., Harris, P., Kosik, K.S., Kurnit, D.M. and Donlon, T.A. (1986) Identification of cDNA Clones for the Human Microtubule-Associated Protein Tau and Chromosomal Localization of the Genes for Tau and Microtubule-Associated Protein 2. Molecular Brain Research, 1, 271-280. [Google Scholar] [CrossRef] [PubMed]
[10] Kumar, M., Quittot, N., Dujardin, S., Schlaffner, C.N., Viode, A., Wiedmer, A., et al. (2024) Alzheimer Proteopathic Tau Seeds Are Biochemically a Forme fruste of Mature Paired Helical Filaments. Brain, 147, 637-648. [Google Scholar] [CrossRef] [PubMed]
[11] Jones, S.L. and Svitkina, T.M. (2016) Axon Initial Segment Cytoskeleton: Architecture, Development, and Role in Neuron Polarity. Neural Plasticity, 2016, Article ID: 6808293. [Google Scholar] [CrossRef] [PubMed]
[12] Di Lorenzo, D. (2024) Tau Protein and Tauopathies: Exploring Tau Protein-Protein and Microtubule Interactions, Cross‐interactions and Therapeutic Strategies. ChemMedChem, 19, e202400180. [Google Scholar] [CrossRef] [PubMed]
[13] Chai, Y., Li, D., Gong, W., Ke, J., Tian, D., Chen, Z., et al. (2024) A Plant Flavonol and Genetic Suppressors Rescue a Pathogenic Mutation Associated with Kinesin in Neurons. Proceedings of the National Academy of Sciences of the United States of America, 121, e2311936121. [Google Scholar] [CrossRef] [PubMed]
[14] Luo, G., Chen, L., Jacutin-Porte, S., Han, Y., Burton, C.R., Xiao, H., et al. (2023) Structure-Activity Relationship (SAR) Studies on Substituted N-(Pyridin-3-Yl)-2-Amino-Isonicotinamides as Highly Potent and Selective Glycogen Synthase Kinase-3 (GSK-3) Inhibitors. Bioorganic & Medicinal Chemistry Letters, 81, Article ID: 129143. [Google Scholar] [CrossRef] [PubMed]
[15] Tanaka, T., Ohashi, S., Takashima, A. and Kobayashi, S. (2022) Dendritic Distribution of CDK5 mRNA and P35 MRNA, and a Glutamate-Responsive Increase of CDK5/p25 Complex Contribute to Tau Hyperphosphorylation. Biochimica et Biophysica Acta (BBA)—General Subjects, 1866, Article ID: 130135. [Google Scholar] [CrossRef] [PubMed]
[16] He, Y., Wang, Y., Li, X., Qi, Y., Qu, Z. and Hu, Y. (2024) Lycium Barbarum Polysaccharides Improves Cognitive Functions in ICV-STZ-Induced Alzheimer’s Disease Mice Model by Improving the Synaptic Structural Plasticity and Regulating IRS1/PI3K/AKT Signaling Pathway. NeuroMolecular Medicine, 26, Article No. 15. [Google Scholar] [CrossRef] [PubMed]
[17] Meur, S. and Karati, D. (2024) Fyn Kinase in Alzheimer’s Disease: Unraveling Molecular Mechanisms and Therapeutic Implications. Molecular Neurobiology, 62, 643-660. [Google Scholar] [CrossRef] [PubMed]
[18] Shen, Z., Sun, D., Savastano, A., Varga, S.J., Cima-Omori, M., Becker, S., et al. (2023) Multivalent Tau/PSD-95 Interactions Arrest in Vitro Condensates and Clusters Mimicking the Postsynaptic Density. Nature Communications, 14, Article No. 6839. [Google Scholar] [CrossRef] [PubMed]
[19] Kyalu Ngoie Zola, N., Balty, C., Pyr dit Ruys, S., Vanparys, A.A.T., Huyghe, N.D.G., Herinckx, G., et al. (2023) Specific Post-Translational Modifications of Soluble Tau Protein Distinguishes Alzheimer’s Disease and Primary Tauopathies. Nature Communications, 14, Article No. 3706. [Google Scholar] [CrossRef] [PubMed]
[20] Ye, H., Han, Y., Li, P., Su, Z. and Huang, Y. (2022) The Role of Post-Translational Modifications on the Structure and Function of Tau Protein. Journal of Molecular Neuroscience, 72, 1557-1571. [Google Scholar] [CrossRef] [PubMed]
[21] 黄颖, 李雪, 高伟, 等. 泛素连接酶和去泛素化酶在阿尔茨海默病中的研究进展[J]. 生命科学, 2024, 36(5): 629-636.
[22] Chen, Y. and Yu, Y. (2023) Tau and Neuroinflammation in Alzheimer’s Disease: Interplay Mechanisms and Clinical Translation. Journal of Neuroinflammation, 20, Article No. 165. [Google Scholar] [CrossRef] [PubMed]
[23] Islam, T., Hill, E., Abrahamson, E.E., Servaes, S., Smirnov, D.S., Zeng, X., Sehrawat, A., et al. (2025). Phospho-Tau Serine-262 and Serine-356 as Biomarkers of Pre-Tangle Soluble Tau Assemblies in Alzheimer’s Disease. Nature Medicine, 31, 574-588.
[24] Merino-Serrais, P., Soria, J.M., Arrabal, C.A., Ortigado-López, A., Esparza, M.Á.G., Muñoz, A., et al. (2025) Protein Tau Phosphorylation in the Proline Rich Region and Its Implication in the Progression of Alzheimer’s Disease. Experimental Neurology, 383, Article ID: 115049. [Google Scholar] [CrossRef] [PubMed]
[25] Maitra, S. and Vincent, B. (2022) Cdk5-p25 as a Key Element Linking Amyloid and Tau Pathologies in Alzheimer’s Disease: Mechanisms and Possible Therapeutic Interventions. Life Sciences, 308, Article ID: 120986. [Google Scholar] [CrossRef] [PubMed]
[26] Kim, J., Tadros, B., Liang, Y.H., Kim, Y., Lasagna-Reeves, C., Sonn, J.Y., et al. (2024) TYK2 Regulates Tau Levels, Phosphorylation and Aggregation in a Tauopathy Mouse Model. Nature Neuroscience, 27, 2417-2429. [Google Scholar] [CrossRef] [PubMed]
[27] Wojdała, A.L., Bellomo, G., Gaetani, L., Teunissen, C.E., Parnetti, L. and Chiasserini, D. (2025) Immunoassay Detection of Multiphosphorylated Tau Proteoforms as Cerebrospinal Fluid and Plasma Alzheimer’s Disease Biomarkers. Nature Communications, 16, Article No. 214. [Google Scholar] [CrossRef] [PubMed]
[28] Huang, Y., Wen, J., Ramirez, L., Gümüşdil, E., Pokhrel, P., Man, V.H., et al. (2023) Methylene Blue Accelerates Liquid-To-Gel Transition of Tau Condensates Impacting Tau Function and Pathology. Nature Communications, 14, Article No. 5444. [Google Scholar] [CrossRef] [PubMed]
[29] 王宗宝, 李森. Tau蛋白的传播扩散与相关免疫反应的研究进展[J]. 北京师范大学学报(自然科学版), 2023, 59(4): 542-547.
[30] Dickson, J.R., Kruse, C., Montagna, D.R., Finsen, B. and Wolfe, M.S. (2013) Alternative Polyadenylation and MIR‐34 Family Members Regulate Tau Expression. Journal of Neurochemistry, 127, 739-749. [Google Scholar] [CrossRef] [PubMed]
[31] Kang, S.S., Meng, L., Zhang, X., Wu, Z., Mancieri, A., Xie, B., et al. (2022) Tau Modification by the Norepinephrine Metabolite DOPEGAL Stimulates Its Pathology and Propagation. Nature Structural & Molecular Biology, 29, 292-305. [Google Scholar] [CrossRef] [PubMed]
[32] Fowler, S.L., Behr, T.S., Turkes, E., O’Brien, D.P., Cauhy, P.M., Rawlinson, I., et al. (2024) Tau Filaments Are Tethered within Brain Extracellular Vesicles in Alzheimer’s Disease. Nature Neuroscience, 28, 40-48. [Google Scholar] [CrossRef] [PubMed]
[33] Chu, D., Yang, X., Wang, J., Zhou, Y., Gu, J., Miao, J., et al. (2023) Tau Truncation in the Pathogenesis of Alzheimer’s Disease: A Narrative Review. Neural Regeneration Research, 19, 1221-1232. [Google Scholar] [CrossRef] [PubMed]
[34] Ayers, J.I., Giasson, B.I. and Borchelt, D.R. (2018) Prion-like Spreading in Tauopathies. Biological Psychiatry, 83, 337-346. [Google Scholar] [CrossRef] [PubMed]
[35] Leyns, C.E.G. and Holtzman, D.M. (2017) Glial Contributions to Neurodegeneration in Tauopathies. Molecular Neurodegeneration, 12, Article No. 50. [Google Scholar] [CrossRef] [PubMed]
[36] 郭笑迪, 张国新, 彭琴玉, 等. Tau蛋白聚集体促进小胶质细胞活化的机制研究[J]. 卒中与神经疾病, 2023, 30(5): 429-432, 439.
[37] Nguyen, A.T., Wang, K., Hu, G., Wang, X., Miao, Z., Azevedo, J.A., et al. (2020) APOE and TREM2 Regulate Amyloid-Responsive Microglia in Alzheimer’s Disease. Acta Neuropathologica, 140, 477-493. [Google Scholar] [CrossRef] [PubMed]
[38] McQuade, A., Kang, Y.J., Hasselmann, J., Jairaman, A., Sotelo, A., Coburn, M., et al. (2020) Gene Expression and Functional Deficits Underlie TREM2-Knockout Microglia Responses in Human Models of Alzheimer’s Disease. Nature Communications, 11, Article No. 5370. [Google Scholar] [CrossRef] [PubMed]
[39] Lee, C.Y.D., Daggett, A., Gu, X., Jiang, L., Langfelder, P., Li, X., et al. (2018) Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer’s Disease Models. Neuron, 97, 1032-1048.e5. [Google Scholar] [CrossRef] [PubMed]
[40] Gratuze, M., Chen, Y., Parhizkar, S., Jain, N., Strickland, M.R., Serrano, J.R., et al. (2021) Activated Microglia Mitigate Aβ-Associated Tau Seeding and Spreading. Journal of Experimental Medicine, 218, e20210542. [Google Scholar] [CrossRef] [PubMed]
[41] Gratuze, M., Leyns, C.E.G., Sauerbeck, A.D., St-Pierre, M., Xiong, M., Kim, N., et al. (2020) Impact of TREM2R47H Variant on Tau Pathology-Induced Gliosis and Neurodegeneration. Journal of Clinical Investigation, 130, 4954-4968. [Google Scholar] [CrossRef] [PubMed]
[42] Pascoal, T.A., Benedet, A.L., Ashton, N.J., Kang, M.S., Therriault, J., Chamoun, M., et al. (2021) Microglial Activation and Tau Propagate Jointly across Braak Stages. Nature Medicine, 27, 1592-1599. [Google Scholar] [CrossRef] [PubMed]
[43] Udeochu, J.C., Amin, S., Huang, Y., Fan, L., Torres, E.R.S., Carling, G.K., et al. (2023) Tau Activation of Microglial cGAS-IFN Reduces MEF2C-Mediated Cognitive Resilience. Nature Neuroscience, 26, 737-750. [Google Scholar] [CrossRef] [PubMed]
[44] Busche, M.A. and Hyman, B.T. (2020) Synergy between Amyloid-Β and Tau in Alzheimer’s Disease. Nature Neuroscience, 23, 1183-1193. [Google Scholar] [CrossRef] [PubMed]
[45] Roemer-Cassiano, S.N., Wagner, F., Evangelista, L., Rauchmann, B., Dehsarvi, A., Steward, A., et al. (2025) Amyloid-associated Hyperconnectivity Drives Tau Spread across Connected Brain Regions in Alzheimer’s Disease. Science Translational Medicine, 17, eadp2564. [Google Scholar] [CrossRef] [PubMed]
[46] Gallego-Rudolf, J., Wiesman, A.I., Pichet Binette, A., Villeneuve, S. and Baillet, S. (2024) Synergistic Association of Aβ and Tau Pathology with Cortical Neurophysiology and Cognitive Decline in Asymptomatic Older Adults. Nature Neuroscience, 27, 2130-2137. [Google Scholar] [CrossRef] [PubMed]
[47] Capilla-López, M.D., Deprada, A., Andrade-Talavera, Y., Martínez-Gallego, I., Coatl-Cuaya, H., Sotillo, P., et al. (2025) Synaptic Vulnerability to Amyloid-β and Tau Pathologies Differentially Disrupts Emotional and Memory Neural Circuits. Molecular Psychiatry.
[48] Johnson & Johnson (2025) Johnson & Johnson’s Posdinemab and Tau Active Immunotherapy Receives US FDA Fast Track Designation for the Treatment of Alzheimer’s Disease.
https://www.prnewswire.com/news-releases/johnson--johnsons-posdinemab-and-tau-active-immunotherapy-receive-us-fda-fast-track-designations-for-the-treatment-of-alzheimers-disease-302345029.html
[49] Guo, Y., Cai, C., Zhang, B., Tan, B., Tang, Q., Lei, Z., et al. (2024) Targeting USP11 Regulation by a Novel Lithium-Organic Coordination Compound Improves Neuropathologies and Cognitive Functions in Alzheimer Transgenic Mice. EMBO Molecular Medicine, 16, 2856-2881. [Google Scholar] [CrossRef] [PubMed]
[50] Benn, J., Cheng, S., Keeling, S., Smith, A.E., Vaysburd, M.J., Böken, D., et al. (2024) Aggregate-Selective Removal of Pathological Tau by Clustering-Activated Degraders. Science, 385, 1009-1016. [Google Scholar] [CrossRef] [PubMed]
[51] Miller, L.V.C., Papa, G., Vaysburd, M., Cheng, S., Sweeney, P.W., Smith, A., et al. (2024) Co-Opting Templated Aggregation to Degrade Pathogenic Tau Assemblies and Improve Motor Function. Cell, 187, 5967-5980.e17. [Google Scholar] [CrossRef] [PubMed]
[52] Hu, Z., Yang, J., Zhang, S., Li, M., Zuo, C., Mao, C., et al. (2024) AAV Mediated Carboxyl Terminus of Hsp70 Interacting Protein Overexpression Mitigates the Cognitive and Pathological Phenotypes of APP/PS1 Mice. Neural Regeneration Research, 20, 253-264. [Google Scholar] [CrossRef] [PubMed]
[53] Jia, N., Ganesan, D., Guan, H., Jeong, Y.Y., Han, S., Rajapaksha, G., et al. (2024) Mitochondrial Bioenergetics Stimulates Autophagy for Pathological MAPT/tau Clearance in Tauopathy Neurons. Autophagy, 21, 54-79. [Google Scholar] [CrossRef] [PubMed]
[54] Vrechi, T.A.M., Guarache, G.C., Oliveira, R.B., Guedes, E.D.C., Erustes, A.G., Leão, A.H.F.F., et al. (2025) Cannabidiol-Induced Autophagy Ameliorates Tau Protein Clearance. Neurotoxicity Research, 43, Article No. 8. [Google Scholar] [CrossRef] [PubMed]
[55] Huang, K., Hsiao, I., Huang, C., Huang, C., Chang, H., Huang, S., et al. (2025) Alzheimer’s & Dementia, 21, e14297. [Google Scholar] [CrossRef] [PubMed]
[56] Warmenhoven, N., Salvadó, G., Janelidze, S., Mattsson-Carlgren, N., Bali, D., Orduña Dolado, A., et al. (2024) A Comprehensive Head-To-Head Comparison of Key Plasma Phosphorylated Tau 217 Biomarker Tests. Brain, 148, 416-431. [Google Scholar] [CrossRef] [PubMed]
[57] 林璐, 马辛, 王刚, 等. 中国阿尔茨海默病早期预防指南(2024) [J]. 阿尔茨海默病及相关病杂志, 2024, 7(3): 168-175.