Clinical Medicine Research

Submit a Manuscript

Publishing with us to make your research visible to the widest possible audience.

Propose a Special Issue

Building a community of authors and readers to discuss the latest research and develop new ideas.

Research Progress of Microglia in the Intervention Effect of Alzheimer's Disease

Alzheimer's disease (AD) is a degenerative disease of the central nervous system characterized by an insidious onset and progressive worsening of cognitive function. The main pathological features of AD are β-amyloid (Aβ) plaques, neuroprogenitor fibril tangles (NFT) formed by hyperphosphorylated Tau proteins, and other pathological features. In addition, there is growing evidence that AD is strongly associated with microglia activation, due to the fact that most of the risk genes for AD are highly expressed by microglia in the brain. The category of microglia is mainly depending on the milieu in which they become activated and the factors they are stimulated. In the development of AD, microglia can be activated to the M1 type to exert neuroinflammatory effects by producing various pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 to induce neurotoxicity, and to the M2 type to exert anti-inflammation effects through enhancing the expression of neurotrophin, IL-4, and IL-6, and accelerate the clearance of Aβ plaques, which is believed to be promising molecules in AD therapy. This paper summarizes the mechanisms of microglia in AD and reviews the activation of microglia, the triggering receptor expressed on myeloid cells 2 (TREM2), disease-associated microglia (DAM), and gut microbiota to identify new therapeutic targets for AD, which currently lacks effective interventions.

Alzheimer's Disease, Microglia, Neuroinflammation, TREM2, DAM, Gut Microbiota

APA Style

Tianying Fang, Caiping Han, Qingli Song, Yaning Hao, Wei Yuan, et al. (2023). Research Progress of Microglia in the Intervention Effect of Alzheimer's Disease. Clinical Medicine Research, 12(4), 82-87. https://doi.org/10.11648/j.cmr.20231204.15

ACS Style

Tianying Fang; Caiping Han; Qingli Song; Yaning Hao; Wei Yuan, et al. Research Progress of Microglia in the Intervention Effect of Alzheimer's Disease. Clin. Med. Res. 2023, 12(4), 82-87. doi: 10.11648/j.cmr.20231204.15

AMA Style

Tianying Fang, Caiping Han, Qingli Song, Yaning Hao, Wei Yuan, et al. Research Progress of Microglia in the Intervention Effect of Alzheimer's Disease. Clin Med Res. 2023;12(4):82-87. doi: 10.11648/j.cmr.20231204.15

Copyright © 2023 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. J. M. Tublin, J. M. Adelstein, F. Del Monte, C. K. Combs, & L. E. Wold. (2019). Getting to the Heart of Alzheimer Disease. Circ Res, 124 (1): 142-149. doi: 10.1161/CIRCRESAHA.118.313563.
2. H. S. Kwon, & S. H. Koh. (2020). Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener, 9 (1): 42. doi: 10.1186/s40035-020-00221-2.
3. F. Ginhoux, M. Greter, M. Leboeuf, S. Nandi, P. See, S. Gokhan,... M. Merad. (2010). Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science, 330 (6005): 841-845. doi: 10.1126/science.1194637.
4. S. A. Wolf, H. W. Boddeke, & H. Kettenmann. (2017). Microglia in Physiology and Disease. Annu Rev Physiol, 79: 619-643. doi: 10.1146/annurev-physiol-022516-034406.
5. H. Keren-Shaul, A. Spinrad, A. Weiner, O. Matcovitch-Natan, R. Dvir-Szternfeld, T. K. Ulland,... I. Amit. (2017). A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell, 169 (7): 1276-1290 e1217. doi: 10.1016/j.cell.2017.05.018.
6. Q. Li, Z. Cheng, L. Zhou, S. Darmanis, N. F. Neff, J. Okamoto,... B. A. Barres. (2019). Developmental Heterogeneity of Microglia and Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing. Neuron, 101 (2): 207-223 e210. doi: 10.1016/j.neuron.2018.12.006.
7. Z. Yin, S. Herron, S. Silveira, K. Kleemann, C. Gauthier, D. Mallah, O. Butovsky. (2023). Identification of a protective microglial state mediated by miR-155 and interferon-gamma signaling in a mouse model of Alzheimer's disease. Nat Neurosci. doi: 10.1038/s41593-023-01355-y.
8. P. Yuan, C. Condello, C. D. Keene, Y. Wang, T. D. Bird, S. M. Paul, J. Grutzendler. (2016). TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy. Neuron, 90 (4): 724-739. doi: 10.1016/j.neuron.2016.05.003.
9. A. A. de Castro, F. V. Soares, A. F. Pereira, D. A. Polisel, M. S. Caetano, D. H. S. Leal,... T. C. Ramalho. (2019). Non-conventional compounds with potential therapeutic effects against Alzheimer's disease. Expert Rev Neurother, 19 (5): 375-395. doi: 10.1080/14737175.2019.1608823.
10. A. Gustavsson, C. Green, R. W. Jones, H. Forstl, D. Simsek, F. de Reydet de Vulpillieres,... A. Wimo. (2017). Current issues and future research priorities for health economic modelling across the full continuum of Alzheimer's disease. Alzheimers Dement, 13 (3): 312-321. doi: 10.1016/j.jalz.2016.12.005.
11. Y. Q. Wang, R. X. Jia, J. H. Liang, J. Li, S. Qian, J. Y. Li, & Y. Xu. (2019). Dementia in China (2015-2050) estimated using the 1% population sampling survey in 2015. Geriatr Gerontol Int, 19 (11): 1096-1100. doi: 10.1111/ggi.13778.
12. F. Kametani, & M. Hasegawa. (2018). Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease. Front Neurosci, 12: 25. doi: 10.3389/fnins.2018.00025.
13. H. Zhang, W. Wei, M. Zhao, L. Ma, X. Jiang, H. Pei,... H. Li. (2021). Interaction between Abeta and Tau in the Pathogenesis of Alzheimer's Disease. Int J Biol Sci, 17 (9): 2181-2192. doi: 10.7150/ijbs.57078.
14. W. H. Zheng, S. Bastianetto, F. Mennicken, W. Ma, & S. Kar. (2002). Amyloid beta peptide induces tau phosphorylation and loss of cholinergic neurons in rat primary septal cultures. Neuroscience, 115 (1): 201-211. doi: 10.1016/s0306-4522(02)00404-9.
15. E. D. Roberson, K. Scearce-Levie, J. J. Palop, F. Yan, I. H. Cheng, T. Wu,... L. Mucke. (2007). Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science, 316 (5825): 750-754. doi: 10.1126/science.1141736.
16. M. T. Heneka, M. J. Carson, J. El Khoury, G. E. Landreth, F. Brosseron, D. L. Feinstein, M. P. Kummer. (2015). Neuroinflammation in Alzheimer's disease. Lancet Neurol, 14 (4): 388-405. doi: 10.1016/S1474-4422(15)70016-5.
17. Y. Zhang, Z. Dong, & W. Song. (2020). NLRP3 inflammasome as a novel therapeutic target for Alzheimer's disease. Signal Transduct Target Ther, 5 (1): 37. doi: 10.1038/s41392-020-0145-7.
18. S. D. Brydges, L. Broderick, M. D. McGeough, C. A. Pena, J. L. Mueller, & H. M. Hoffman. (2013). Divergence of IL-1, IL-18, and cell death in NLRP3 inflammasomopathies. J Clin Invest, 123 (11): 4695-4705. doi: 10.1172/JCI71543.
19. C. Ising, C. Venegas, S. Zhang, H. Scheiblich, S. V. Schmidt, A. Vieira-Saecker,... M. T. Heneka. (2019). NLRP3 inflammasome activation drives tau pathology. Nature, 575 (7784): 669-673. doi: 10.1038/s41586-019-1769-z.
20. Y Cui, X Lu, & F Li. (2020). The role of disease-related Microglia in the pathogenesis of Alzheimer's disease. Chinese Journal of Comparative Medicine, 30 (05): 132-136. doi: 10.3969/j.issn.1671-7856.2020.05.021.
21. N. Wang, H. Liang, & K. Zen. (2014). Molecular mechanisms that influence the macrophage m1-m2 polarization balance. Front Immunol, 5: 614. doi: 10.3389/fimmu.2014.00614.
22. S. Merighi, M. Nigro, A. Travagli, & S. Gessi. (2022). Microglia and Alzheimer's Disease. Int J Mol Sci, 23 (21). doi: 10.3390/ijms232112990.
23. E. Sun, A. Motolani, L. Campos, & T. Lu. (2022). The Pivotal Role of NF-kB in the Pathogenesis and Therapeutics of Alzheimer's Disease. Int J Mol Sci, 23 (16). doi: 10.3390/ijms23168972.
24. X. Jin, M. Y. Liu, D. F. Zhang, X. Zhong, K. Du, P. Qian,... M. J. Wei. (2019). Baicalin mitigates cognitive impairment and protects neurons from microglia-mediated neuroinflammation via suppressing NLRP3 inflammasomes and TLR4/NF-kappaB signaling pathway. CNS Neurosci Ther, 25 (5): 575-590. doi: 10.1111/cns.13086.
25. C. Wang, L. Fan, R. R. Khawaja, B. Liu, L. Zhan, L. Kodama, L. Gan. (2022). Microglial NF-kappaB drives tau spreading and toxicity in a mouse model of tauopathy. Nat Commun, 13 (1): 1969. doi: 10.1038/s41467-022-29552-6.
26. T. Jiang, L. Tan, Q. Chen, M. S. Tan, J. S. Zhou, X. C. Zhu,... J. T. Yu. (2016). A rare coding variant in TREM2 increases risk for Alzheimer's disease in Han Chinese. Neurobiol Aging, 42: 217 e211-213. doi: 10.1016/j.neurobiolaging.2016.02.023.
27. S. Carmona, K. Zahs, E. Wu, K. Dakin, J. Bras, & R. Guerreiro. (2018). The role of TREM2 in Alzheimer's disease and other neurodegenerative disorders. Lancet Neurol, 17 (8): 721-730. doi: 10.1016/S1474-4422(18)30232-1.
28. K. Kurisu, Z. Zheng, J. Y. Kim, J. Shi, A. Kanoke, J. Liu,... M. A. Yenari. (2019). Triggering receptor expressed on myeloid cells-2 expression in the brain is required for maximal phagocytic activity and improved neurological outcomes following experimental stroke. J Cereb Blood Flow Metab, 39 (10): 1906-1918. doi: 10.1177/0271678X18817282.
29. Q. Qin, Z. Teng, C. Liu, Q. Li, Y. Yin, & Y. Tang. (2021). TREM2, microglia, and Alzheimer's disease. Mech Ageing Dev, 195: 111438. doi: 10.1016/j.mad.2021.111438.
30. S. H. Lee, W. J. Meilandt, L. Xie, V. D. Gandham, H. Ngu, K. H. Barck, D. V. Hansen. (2021). Trem2 restrains the enhancement of tau accumulation and neurodegeneration by beta-amyloid pathology. Neuron, 109 (8): 1283-1301 e1286. doi: 10.1016/j.neuron.2021.02.010.
31. B Wei, T Jiang, H Lian, R Duna, X Fu, & Y Zhang. (2022). Alzheimer's Disease Susceptibility Gene TREM2 Ameliorates Neuroinflammation by Inhibition of Microglial NLRP3 Inflammasome Activation. Chinese Journal of Clinical Neurosciences, 30 (05): 487-492.
32. R. Y. Li, Q. Qin, H. C. Yang, Y. Y. Wang, Y. X. Mi, Y. S. Yin,... Y. Tang. (2022). TREM2 in the pathogenesis of AD: a lipid metabolism regulator and potential metabolic therapeutic target. Mol Neurodegener, 17 (1): 40. doi: 10.1186/s13024-022-00542-y.
33. S. Rangaraju, E. B. Dammer, S. A. Raza, P. Rathakrishnan, H. Xiao, T. Gao, A. I. Levey. (2018). Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer's disease. Mol Neurodegener, 13 (1): 24. doi: 10.1186/s13024-018-0254-8.
34. Y. Zhou, W. M. Song, P. S. Andhey, A. Swain, T. Levy, K. R. Miller, M. Colonna. (2020). Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease. Nat Med, 26 (1): 131-142. doi: 10.1038/s41591-019-0695-9.
35. J. Qin, R. Li, J. Raes, M. Arumugam, K. S. Burgdorf, C. Manichanh, J. Wang. (2010). A human gut microbial gene catalogue established by metagenomic sequencing. Nature, 464 (7285): 59-65. doi: 10.1038/nature08821.
36. E. M. M. Quigley. (2017). Microbiota-Brain-Gut Axis and Neurodegenerative Diseases. Curr Neurol Neurosci Rep, 17 (12): 94. doi: 10.1007/s11910-017-0802-6.
37. Q. Ma, C. Xing, W. Long, H. Y. Wang, Q. Liu, & R. F. Wang. (2019). Impact of microbiota on central nervous system and neurological diseases: the gut-brain axis. J Neuroinflammation, 16 (1): 53. doi: 10.1186/s12974-019-1434-3.
38. H. Shen, Q. Guan, X. Zhang, C. Yuan, Z. Tan, L. Zhai,... C. Han. (2020). New mechanism of neuroinflammation in Alzheimer's disease: The activation of NLRP3 inflammasome mediated by gut microbiota. Prog Neuropsychopharmacol Biol Psychiatry, 100: 109884. doi: 10.1016/j.pnpbp.2020.109884.
39. D. Abraham, J. Feher, G. L. Scuderi, D. Szabo, A. Dobolyi, M. Cservenak,... Z. Radak. (2019). Exercise and probiotics attenuate the development of Alzheimer's disease in transgenic mice: Role of microbiome. Exp Gerontol, 115: 122-131. doi: 10.1016/j.exger.2018.12.005.