间充质干细胞外泌体通过不同信号通路改善阿尔茨海默病的研究进展
Research Progress on the Improvement of Alzheimer’s Disease by Mesenchymal Stem Cell Exosomes through Different Signaling Pathways
DOI: 10.12677/acm.2025.1551498, PDF,   
作者: 焦庆欣：西安医学院研究生工作部，陕西 西安；刘卫平*：西安医学院第一附属医院神经外科，陕西 西安
关键词: 阿尔兹海默病；间充质干细胞外泌体；信号通路；机制；Alzheimer’s Disease； Mesenchymal Stem Cell Exosomes； Signaling Pathways； Mechanisms
摘要: 阿尔茨海默病(Alzheimer’s Disease, AD)是最普遍的痴呆类型，是一种长期的退行性疾病。在病理学上，它定义为括β淀粉样蛋白(Amyloid-β, Aβ)沉积形成的老年斑(Senile Slaques, SP)和过度磷酸化Tau蛋白导致的神经原纤维缠结(Neurofibrillary Tangle, NFT)。这会导致神经元死亡，尤其是在海马体和皮层中。AD作为一种严重危害老年人健康的神经退行性疾病，目前缺乏有效的根治手段。间充质干细胞外泌体(Mesenchymal Stem Cell-derived Exosomes, MSC-Exos)凭借其独特的生物学特性，在AD治疗领域展现出巨大的治疗潜力。本文旨在阐述间充质干细胞外泌体调控的关键信号通路及其在AD中的作用，为AD的治疗研究提供全面且深入的参考。
Abstract: Alzheimer’s Disease (AD) is the most prevalent type of dementia, representing a long-term degenerative condition. Pathologically, it is characterized by the formation of senile plaques (SP) due to the deposition of amyloid-β (Aβ) and neurofibrillary tangles (NFT) caused by hyperphosphorylated tau protein. These pathological changes lead to neuronal death, particularly in the hippocampus and cortex. As a neurodegenerative disease that severely threatens the health of the elderly, AD currently lacks effective curative treatments. Mesenchymal Stem Cell-derived Exosomes (MSC-Exos) demonstrate significant therapeutic potential in the field of AD treatment due to their unique biological properties. This article aims to elucidate the key signaling pathways regulated by MSC-Exos and their role in AD, providing a comprehensive and in-depth reference for AD treatment research.
文章引用：焦庆欣, 刘卫平. 间充质干细胞外泌体通过不同信号通路改善阿尔茨海默病的研究进展[J]. 临床医学进展, 2025, 15(5): 1330-1336. https://doi.org/10.12677/acm.2025.1551498

参考文献

[1] Testo, A.A., Roundy, G. and Dumas, J.A. (2024) Cognitive Decline in Alzheimer’s Disease. In: Kidd, E.J. and Newhouse, P.A., Eds., Neurobiology of Alzheimer’s Disease, Springer, 181-195. [Google Scholar] [CrossRef] [PubMed]
[2] Zhang, J., Zhang, Y., Wang, J., Xia, Y., Zhang, J. and Chen, L. (2024) Recent Advances in Alzheimer’s Disease: Mechanisms, Clinical Trials and New Drug Development Strategies. Signal Transduction and Targeted Therapy, 9, Article No. 211. [Google Scholar] [CrossRef] [PubMed]
[3] Passeri, E., Elkhoury, K., Morsink, M., Broersen, K., Linder, M., Tamayol, A., et al. (2022) Alzheimer’s Disease: Treatment Strategies and Their Limitations. International Journal of Molecular Sciences, 23, Article 13954. [Google Scholar] [CrossRef] [PubMed]
[4] Khan, S., Barve, K.H. and Kumar, M.S. (2020) Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease. Current Neuropharmacology, 18, 1106-1125. [Google Scholar] [CrossRef] [PubMed]
[5] Zhang, Z.G., Buller, B. and Chopp, M. (2019) Exosomes—Beyond Stem Cells for Restorative Therapy in Stroke and Neurological Injury. Nature Reviews Neurology, 15, 193-203. [Google Scholar] [CrossRef] [PubMed]
[6] Lotfy, A., AboQuella, N.M. and Wang, H. (2023) Mesenchymal Stromal/Stem Cell (MSC)-Derived Exosomes in Clinical Trials. Stem Cell Research & Therapy, 14, Article No. 66. [Google Scholar] [CrossRef] [PubMed]
[7] Wan, F. and Lenardo, M.J. (2009) The Nuclear Signaling of NF-κB: Current Knowledge, New Insights, and Future Perspectives. Cell Research, 20, 24-33. [Google Scholar] [CrossRef] [PubMed]
[8] Camandola, S. and Mattson, M.P. (2007) NF-κB as a Therapeutic Target in Neurodegenerative Diseases. Expert Opinion on Therapeutic Targets, 11, 123-132. [Google Scholar] [CrossRef] [PubMed]
[9] Srinivasan, M. and Lahiri, D.K. (2015) Significance of NF-κB as a Pivotal Therapeutic Target in the Neurodegenerative Pathologies of Alzheimer’s Disease and Multiple Sclerosis. Expert Opinion on Therapeutic Targets, 19, 471-487. [Google Scholar] [CrossRef] [PubMed]
[10] Kubota, K., Nakano, M., Kobayashi, E., Mizue, Y., Chikenji, T., Otani, M., et al. (2018) An Enriched Environment Prevents Diabetes-Induced Cognitive Impairment in Rats by Enhancing Exosomal miR-146a Secretion from Endogenous Bone Marrow-Derived Mesenchymal Stem Cells. PLOS ONE, 13, e0204252. [Google Scholar] [CrossRef] [PubMed]
[11] Nakano, M., Kubota, K., Kobayashi, E., Chikenji, T.S., Saito, Y., Konari, N., et al. (2020) Bone Marrow-Derived Mesenchymal Stem Cells Improve Cognitive Impairment in an Alzheimer’s Disease Model by Increasing the Expression of MicroRNA-146a in Hippocampus. Scientific Reports, 10, Article No. 10772. [Google Scholar] [CrossRef] [PubMed]
[12] Buendia, I., Michalska, P., Navarro, E., Gameiro, I., Egea, J. and León, R. (2016) Nrf2-ARE Pathway: An Emerging Target against Oxidative Stress and Neuroinflammation in Neurodegenerative Diseases. Pharmacology & Therapeutics, 157, 84-104. [Google Scholar] [CrossRef] [PubMed]
[13] Osama, A., Zhang, J., Yao, J., Yao, X. and Fang, J. (2020) Nrf2: A Dark Horse in Alzheimer’s Disease Treatment. Ageing Research Reviews, 64, Article ID: 101206. [Google Scholar] [CrossRef] [PubMed]
[14] Loboda, A., Damulewicz, M., Pyza, E., Jozkowicz, A. and Dulak, J. (2016) Role of Nrf2/HO-1 System in Development, Oxidative Stress Response and Diseases: An Evolutionarily Conserved Mechanism. Cellular and Molecular Life Sciences, 73, 3221-3247. [Google Scholar] [CrossRef] [PubMed]
[15] Wang, H., Liu, Y., Li, J., Wang, T., Hei, Y., Li, H., et al. (2021) Tail-Vein Injection of MSC-Derived Small Extracellular Vesicles Facilitates the Restoration of Hippocampal Neuronal Morphology and Function in APP / PS1 Mice. Cell Death Discovery, 7, Article No. 230. [Google Scholar] [CrossRef] [PubMed]
[16] Ventriglia, M., Zanardini, R., Bonomini, C., Zanetti, O., Volpe, D., Pasqualetti, P., et al. (2013) Serum Brain-Derived Neurotrophic Factor Levels in Different Neurological Diseases. BioMed Research International, 2013, Article ID: 901082. [Google Scholar] [CrossRef] [PubMed]
[17] Binder, D.K. and Scharfman, H.E. (2004) Brain-Derived Neurotrophic Factor. Growth Factors, 22, 123-131. [Google Scholar] [CrossRef] [PubMed]
[18] Lu, B., Nagappan, G., Guan, X., Nathan, P.J. and Wren, P. (2013) BDNF-Based Synaptic Repair as a Disease-Modifying Strategy for Neurodegenerative Diseases. Nature Reviews Neuroscience, 14, 401-416. [Google Scholar] [CrossRef] [PubMed]
[19] Ng, T.K.S., Ho, C.S.H., Tam, W.W.S., Kua, E.H. and Ho, R.C. (2019) Decreased Serum Brain-Derived Neurotrophic Factor (BDNF) Levels in Patients with Alzheimer’s Disease (AD): A Systematic Review and Meta-Analysis. International Journal of Molecular Sciences, 20, Article 257. [Google Scholar] [CrossRef] [PubMed]
[20] Wang, Z., Xiang, J., Liu, X., Yu, S.P., Manfredsson, F.P., Sandoval, I.M., et al. (2019) Deficiency in BDNF/TrkB Neurotrophic Activity Stimulates δ-Secretase by Upregulating C/EBPβ in Alzheimer’s Disease. Cell Reports, 28, 655-669.e5. [Google Scholar] [CrossRef] [PubMed]
[21] Peng, D., Liu, T., Lu, H., Zhang, L., Chen, H., Huang, Y., et al. (2024) Intranasal Delivery of Engineered Extracellular Vesicles Loaded with miR-206-3p Antagomir Ameliorates Alzheimer’s Disease Phenotypes. Theranostics, 14, 7623-7644. [Google Scholar] [CrossRef] [PubMed]
[22] Liu, S., Fan, M., Xu, J., Yang, L., Qi, C., Xia, Q., et al. (2022) Exosomes Derived from Bone-Marrow Mesenchymal Stem Cells Alleviate Cognitive Decline in AD-Like Mice by Improving BDNF-Related Neuropathology. Journal of Neuroinflammation, 19, Article No. 35. [Google Scholar] [CrossRef] [PubMed]
[23] Cui, M., Yoshimori, T. and Nakamura, S. (2022) Autophagy System as a Potential Therapeutic Target for Neurodegenerative Diseases. Neurochemistry International, 155, Article ID: 105308. [Google Scholar] [CrossRef] [PubMed]
[24] Fang, E.F., Hou, Y., Palikaras, K., Adriaanse, B.A., Kerr, J.S., Yang, B., et al. (2019) Mitophagy Inhibits Amyloid-β and Tau Pathology and Reverses Cognitive Deficits in Models of Alzheimer’s Disease. Nature Neuroscience, 22, 401-412. [Google Scholar] [CrossRef] [PubMed]
[25] Toyama, E.Q., Herzig, S., Courchet, J., Lewis, T.L., Losón, O.C., Hellberg, K., et al. (2016) AMP-Activated Protein Kinase Mediates Mitochondrial Fission in Response to Energy Stress. Science, 351, 275-281. [Google Scholar] [CrossRef] [PubMed]
[26] Mairet-Coello, G., Courchet, J., Pieraut, S., Courchet, V., Maximov, A. and Polleux, F. (2013) The CAMKK2-AMPK Kinase Pathway Mediates the Synaptotoxic Effects of Aβ Oligomers through Tau Phosphorylation. Neuron, 78, 94-108. [Google Scholar] [CrossRef] [PubMed]
[27] Mueed, Z., Tandon, P., Maurya, S.K., Deval, R., Kamal, M.A. and Poddar, N.K. (2019) Tau and mTOR: The Hotspots for Multifarious Diseases in Alzheimer’s Development. Frontiers in Neuroscience, 12, Article 1017. [Google Scholar] [CrossRef] [PubMed]
[28] Ebrahim, N., Al Saihati, H.A., Alali, Z., Aleniz, F.Q., Mahmoud, S.Y.M., Badr, O.A., et al. (2024) Exploring the Molecular Mechanisms of MSC-Derived Exosomes in Alzheimer’s Disease: Autophagy, Insulin and the PI3K/Akt/mTOR Signaling Pathway. Biomedicine & Pharmacotherapy, 176, Article ID: 116836. [Google Scholar] [CrossRef] [PubMed]
[29] Maurice, M.M. and Angers, S. (2025) Mechanistic Insights into Wnt-β-Catenin Pathway Activation and Signal Transduction. Nature Reviews Molecular Cell Biology, 26, 371-388. [Google Scholar] [CrossRef] [PubMed]
[30] Jia, L., Piña-Crespo, J. and Li, Y. (2019) Restoring Wnt/β-Catenin Signaling Is a Promising Therapeutic Strategy for Alzheimer’s Disease. Molecular Brain, 12, Article No. 104. [Google Scholar] [CrossRef] [PubMed]
[31] Maguschak, K.A. and Ressler, K.J. (2012) A Role for Wnt/β-Catenin Signaling in the Neural Mechanisms of Behavior. Journal of Neuroimmune Pharmacology, 7, 763-773. [Google Scholar] [CrossRef] [PubMed]
[32] Sha, S., Shen, X., Cao, Y. and Qu, L. (2021) Mesenchymal Stem Cells-Derived Extracellular Vesicles Ameliorate Alzheimer’s Disease in Rat Models via the MicroRNA-29c-3p/BACE1 Axis and the Wnt/β-Catenin Pathway. Aging, 13, 15285-15306. [Google Scholar] [CrossRef] [PubMed]

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