Glial Dysfunction in Alzheimer’s Disease: Contributions to Disease Progression, Pathomechanism and Therapeutic Opportunities
Main Article Content
Abstract
Alzheimer’s disease (AD), the most common cause of dementia, remains a major neurodegenerative disorder with an incompletely understood etiology despite decades of research. While beta-amyloid plaques and neurofibrillary tau tangles represent the defining pathological hallmarks of AD, growing evidence indicates that the disease’s progression is profoundly influenced by chronic neuroinflammation. Microglia and astrocytes, which are essential for maintaining neuronal homeostasis, clear plaques, support vascular and synaptic function, undergo a pathological shift in AD from protective regulators to dysfunctional, proinflammatory mediators. This transition is characterized by impaired plaque phagocytosis, excessive cytokine release, oxidative stress, and blood-brain barrier (BBB) disruption, all of which contribute to synaptic loss and neurodegeneration. However, the mechanisms driving glial failure remain poorly defined, leaving unresolved questions about whether neuroinflammation in AD acts as an amplifier of existing pathology or a downstream consequence. This literature review examines recent evidence on microglial and astrocytic dysfunction in AD, evaluates proposed cellular and molecular mechanisms underlying their pathological transformation, and explores the potential for glial-targeted interventions. Emerging research suggests that restoring glial function, rather than solely targeting plaques or tau tangles, may offer a promising strategy to slow or delay AD progression by enhancing plaque clearance, maintaining metabolic and vascular stability, and reducing inflammatory neurotoxicity.
Keywords:
Alzheimer’s disease, microglia, astrocytes, beta-amyloid plaques, neurofibrillary tangles, neuroinflammation, cytokine dysregulation, blood-brain barrier, vascular pathology, therapeutic targets
Article Details
How to Cite
DRESCHNACK, Ina; DRESCHNACK, Paul A..
Glial Dysfunction in Alzheimer’s Disease: Contributions to Disease Progression, Pathomechanism and Therapeutic Opportunities.
Medical Research Archives, [S.l.], v. 14, n. 1, jan. 2026.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/7229>. Date accessed: 24 feb. 2026.
doi: https://doi.org/10.18103/mra.v14i1.7229.
Keywords
Alzheimer's disease, microglia, astrocytes, beta-amyloid plaques, neurofibrillary tangles, neuroinflammation, cytokine dysregulation, blood-brain barrier, vascular pathology, therapeutic targets.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Kiraly, M., Foss, J. F., & Giordano, T. (2023). Neuroinflammation, Its Role in Alzheimer's Disease and Therapeutic Strategies. The journal of prevention of Alzheimer's disease, 10(4), 686–698. https://doi.org/10.14283/jpad.2023.109.
2. Al-Ghraiybah, N. F., Wang, J., Alkhalifa, A. E., Roberts, A. B., Raj, R., Yang, E., & Kaddoumi, A. (2022). Glial Cell-Mediated Neuroinflammation in Alzheimer's Disease. International journal of molecular sciences, 23(18), 10572. https://doi.org/10.3390/ijms231810572
3. Holtzman, D. M., Morris, J. C., & Goate, A. M. (2011). Alzheimer's disease: the challenge of the second century. Science translational medicine, 3(77), 77sr1. https://doi.org/10.1126/scitranslmed.3002369
4. Perl D. P. (2010). Neuropathology of Alzheimer's disease. The Mount Sinai journal of medicine, New York, 77(1), 32–42. https://doi.org/10.1002/msj.20157.
5. Choi, S. B., Kwon, S., Kim, J. H., Ahn, N. H., Lee, J. H., & Yang, S. H. (2023). The Molecular Mechanisms of Neuroinflammation in Alzheimer's Disease: The Consequence of Neural Cell Death. International journal of molecular sciences, 24(14), 11757. https://doi.org/10.3390/ijms241411757
6. Kwon, H. S., & Koh, S. H. (2020). Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Translational neurodegeneration, 9(1), 42. https://doi.org/10.1186/s40035-020-00221-2.
7. Leng, F., Edison, P. Neuroinflammation and microglial activation in Alzheimer's disease: where do we go from here? Nat Rev Neurol 17, 157–172 (2021). https://doi.org/10.1038/s41582-020-00435-y
8. Hong, S., Beja-Glasser, V. F., Nfonoyim, B. M., Frouin, A., Li, S., Ramakrishnan, S., ... & Stevens, B. (2016). Complement and microglia mediate early synapse loss in Alzheimer's mouse models. Science, 352(6286), 712–716. https://doi.org/10.1126/science.aad8373.
9. Gomez-Arboledas, A., Acharya, M. M., & Tenner, A. J. (2021). The Role of Complement in Synaptic Pruning and Neurodegeneration. ImmunoTargets and therapy, 10, 373–386. https://doi.org/10.2147/ITT.S305420
10. Liang, T., Zhang, Y., Wu, S., Chen, Q., & Wang, L. (2022). The Role of NLRP3 Inflammasome in Alzheimer's Disease and Potential Therapeutic Targets. Frontiers in pharmacology, 13, 845185. https://doi.org/10.3389/fphar.2022.845185
11. Ittner, L., Götz, J. Amyloid-β and tau — a toxic pas de deux in Alzheimer's disease. Nat Rev Neurosci 12, 67–72 (2011). https://doi.org/10.1038/nrn2967.
12. Haass, C., Selkoe, D. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide. Nat Rev Mol Cell Biol 8, 101–112 (2007). https://doi.org/10.1038/nrm2101.
13. Shimizu, H., Tosaki, A., Kaneko, K., Hisano, T., Sakurai, T., & Nukina, N. (2008). Crystal structure of an active form of BACE1, an enzyme responsible for amyloid beta protein production. Molecular and cellular biology, 28(11), 3663–3671. https://doi.org/10.1128/MCB.02185-07.
14. Haass, C., Lemere, C. A., Capell, A., Citron, M., Seubert, P., Schenk, D., Lannfelt, L., & Selkoe, D. J. (1995). The Swedish mutation causes early-onset Alzheimer's disease by beta-secretase cleavage within the secretory pathway. Nature medicine, 1(12), 1291–1296. https://doi.org/10.1038/nm1295-1291.
15. Weggen, S., & Beher, D. (2012). Molecular consequences of amyloid precursor protein and presenilin mutations causing autosomal-dominant Alzheimer's disease. Alzheimer's research & therapy, 4(2), 9. https://doi.org/10.1186/alzrt107.
16. Zhang, S., Wang, Z., Cai, F., Zhang, M., Wu, Y., Zhang, J., & Song, W. (2017). BACE1 Cleavage Site Selection Critical for Amyloidogenesis and Alzheimer's Pathogenesis. The Journal of neuroscience: the official journal of the Society for Neuroscience, 37(29), 6915–6925. https://doi.org/10.1523/JNEUROSCI.0340-17.2017.
17. Cole, S. L., & Vassar, R. (2007). The Alzheimer's disease beta-secretase enzyme, ACE1. Molecular neurodegeneration, 2, 22. https://doi.org/10.1186/1750-1326-2-22.
18. Zhang, X., & Song, W. (2013). The role of APP and BACE1 trafficking in APP processing and amyloid-β generation. Alzheimer's research & therapy, 5(5), 46. https://doi.org/10.1186/alzrt211.
19. Selkoe, D.J., Hardy, J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med 8, 595–608 (2016). https://doi.org/10.15252/emmm.201606210.
20. Palop, J., Mucke, L. Amyloid-β–induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks. Nat Neurosci 13, 812–818 (2010). https://doi.org/10.1038/nn.2583.
21. Shankar, G., Li, S., Mehta, T. et al. Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 14, 837–842 (2008). https://doi.org/10.1038/nm1782.
22. Heneka, M. T., Carson, M. J., Khoury, J. E., Landreth, G. E., Brosseron, F., Feinstein, D. L., Jacobs, A. H., Wyss-Coray, T., Vitorica, J., Ransohoff, R. M., Herrup, K., Frautschy, S. A., Finsen, B., Brown, G. C., Verkhratsky, A., Yamanaka, K., Koistinaho, J., Latz, E., Halle, A., . Kummer, M. P. (2015). Neuroinflammation in Alzheimer’s disease. The Lancet Neurology, 14(4), 388–405. https://doi.org/10.1016/s1474-4422(15)70016-5
23. Ulland, T. K., Song, W. M., & Colonna, M. (2017). TREM2 function in Alzheimer’s disease and neurodegeneration. ACS Chemical Neuroscience, 8(4), 809–818. https://doi.org/10.1021/acschemneuro.7b00063.
24. Trejo-Lopez, J. A., Yachnis, A. T., & Prokop, S. (2022). Neuropathology of Alzheimer's Disease. Neurotherapeutics: the journal of the American Society for Experimental NeuroTherapeutics, 19(1), 173–185. https://doi.org/10.1007/s13311-021-01146-y
25. Wang, Y., Mandelkow, E. Tau in physiology and pathology. Nat Rev Neurosci 17, 22–35 (2016). https://doi.org/10.1038/nrn.2015.1.
26. Clavaguera, F., Bolmont, T., Crowther, R. A., Abramowski, D., Frank, S., Probst, A., Fraser, G., Stalder, A. K., Beibel, M., Staufenbiel, M., Jucker, M., Goedert, M., & Tolnay, M. (2009). Transmission and spreading of tauopathy in transgenic mouse brain. Nature Cell Biology, 11(7), 909–913. https://doi.org/10.1038/ncb1901.
27. Goedert, M., Spillantini, M.G. Propagation of Tau aggregates. Mol Brain 10, 18 (2017). https://doi.org/10.1186/s13041-017-0298-7.
28. Pooler, A. M., Phillips, E. C., Lau, D. H., Noble, W., & Hanger, D. P. (2013). Physiological release of endogenous tau is stimulated by neuronal activity. EMBO reports, 14(4), 389–394. https://doi.org/10.1038/embor.2013.15.
29. Cummings, J., Lee, G., Zhong, K., Fonseca, J., & Taghva, K. (2021). Alzheimer's disease drug development pipeline: 2021. Alzheimer's & dementia (New York, N. Y.), 7(1), e12179. https://doi.org/10.1002/trc2.12179.
30. Panza, F., Lozupone, M., Logroscino, G., & Imbimbo, B. P. (2019). A critical appraisal of amyloid-β-targeting therapies for Alzheimer's disease. Nature Reviews. Neurology, 15(2), 73–88. https://doi.org/10.1038/s41582-018-0116-6.
31. Heneka, M. T., Golenbock, D. T., & Latz, E. (2015). Innate immunity in Alzheimer's disease. Nature immunology, 16(3), 229–236. https://doi.org/10.1038/ni.3102.
32. Salter, M., Stevens, B. Microglia emerge as central players in brain disease. Nat Med 23, 1018–1027 (2017). https://doi.org/10.1038/nm.4397.
33. Hansen, D. V., Hanson, J. E., & Sheng, M. (2017). Microglia in Alzheimer’s disease. The Journal of Cell Biology, 217(2), 459–472. https://doi.org/10.1083/jcb.201709069.
34. Basha, S. C., Ramaiah, M. J., & Kosagisharaf, J. R. (2023). Untangling the Role of TREM2 in Conjugation with Microglia in Neuronal Dysfunction: A Hypothesis on a Novel Pathway in the Pathophysiology of Alzheimer's Disease. Journal of Alzheimer's disease: JAD, 94(s1), S319–S333. https://doi.org/10.3233/JAD-221070
35. Dar, N. J., Bhat, J. A., John, U., & Bhat, S. A. (2024). Neuroglia in Neurodegeneration: Exploring Glial Dynamics in Brain Disorders. Neuroglia, 5(4), 488-504. https://doi.org/10.3390/neuroglia5040031.
36. Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., Ulland, T. K., David, E., Baruch, K., Lara-Astaiso, D., Toth, B., Itzkovitz, S., Colonna, M., Schwartz, M., & Amit, I. (2017). A Unique Microglia Type Associated with Restricting the Development of qAlzheimer's Disease. Cell, 169(7), 1276–1290.e17. https://doi.org/10.1016/j.cell.2017.05.018.
37. Wang, S., Mustafa, M., Yuede, C. M., Salazar, S. V., Kong, P., Long, H., Ward, M., Siddiqui, O., Paul, R., Gilfillan, S., Ibrahim, A., Rhinn, H., Tassi, I., Rosenthal, A., Schwabe, T., & Colonna, M. (2020). Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model. The Journal of Experimental Medicine, 217(9). https://doi.org/10.1084/jem.20200785.
38. Heneka, M. T., Kummer, M. P., Stutz, A., Delekate, A., Schwartz, S., Vieira-Saecker, A., Griep, A., Axt, D., Remus, A., Tzeng, T. C., Gelpi, E., Halle, A., Korte, M., Latz, E., & Golenbock, D. T. (2013). NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature, 493(7434), 674–678. https://doi.org/10.1038/nature11729.
39. Yin, J., Zhao, F., Chojnacki, J. E., Fulp, J., Klein, W. L., Zhang, S., & Zhu, X. (2018). NLRP3 Inflammasome Inhibitor Ameliorates Amyloid Pathology in a Mouse Model of Alzheimer's Disease. Molecular neurobiology, 55(3), 1977–1987. https://doi.org/10.1007/s12035-017-0467-9.
40. Cornell, J., Salinas, S., Huang, H. Y., & Zhou, M. (2022). Microglia regulation of synaptic plasticity, learning, and memory. Neural regeneration research, 17(4), 705–716. https://doi.org/10.4103/1673-5374.322423
41. Hamelin, L., Lagarde, J., Dorothée, G., Leroy, C., Labit, M., Comley, R. A., de Souza, L. C., Corne, H., Dauphinot, L., Bertoux, M., Dubois, B., Gervais, P., Colliot, O., Potier, M. C., Bottlaender, M., Sarazin, M., & Clinical IMABio3 team (2016). Early and protective microglial activation in Alzheimer's disease: a prospective study using 18F-DPA-714 PET imaging. Brain: a journal of neurology, 139(Pt 4), 1252–1264. https://doi.org/10.1093/brain/aww017.
42. Rauchmann, B. S., Brendel, M., Franzmeier, N., Trappmann, L., Zaganjori, M., Ersoezlue, E., Morenas-Rodriguez, E., Guersel, S., Burow, L., Kurz, C., Haeckert, J., Tatò, M., Utecht, J., Papazov, B., Pogarell, O., Janowitz, D., Buerger, K., Ewers, M., Palleis, C., Weidinger, E., Perneczky, R. (2022). Microglial Activation and Connectivity in Alzheimer's Disease and Aging. Annals of Neurology, 92(5), 768–781. https://doi.org/10.1002/ana.26465.
43. Wang, Q., Chen, G., Schindler, S. E., Christensen, J., McKay, N. S., Liu, J., Wang, S., Sun, Z., Hassenstab, J., Su, Y., Flores, S., Hornbeck, R., Cash, L., Cruchaga, C., Fagan, A. M., Tu, Z., Morris, J. C., Mintun, M. A., Wang, Y., & Benzinger, T. L. S. (2022). Baseline Microglial Activation Correlates with Brain Amyloidosis and Longitudinal Cognitive Decline in Alzheimer Disease. Neurology(R) neuroimmunology & neuroinflammation, 9(3), e1152. https://doi.org/10.1212/NXI.0000000000001152.
44. Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W. S., Peterson, T. C., Wilton, D. K., Frouin, A., Napier, B. A., Panicker, N., Kumar, M., Buckwalter, M. S., Rowitch, D. H., Dawson, V. L., Dawson, T. M., Stevens, B., Barres, B. A. (2017). Neurotoxic reactive astrocytes are induced by activated microglia. Nature, 541(7638), 481–487. https://doi.org/10.1038/nature21029
45. Oksanen, M., Hyötyläinen, I., Trontti, K., Rolova, T., Wojciechowski, S., Koskuvi, M., Viitanen, M., Levonen, A. L., Hovatta, I., Roybon, L., Lehtonen, Š., Kanninen, K. M., Hämäläinen, R. H., & Koistinaho, J. (2020). NF-E2-related factor 2 activation boosts antioxidant defenses and ameliorates inflammatory and amyloid properties in human Presenilin-1 mutated Alzheimer's disease astrocytes. Glia, 68(3), 589–599. https://doi.org/10.1002/glia.23741.
46. Kwon, Y. I. C., Xie, W., Zhu, H., Xie, J., Shinn, K., Juckel, N., Vince, R., More, S. S., & Lee, M. K. (2021). Γ-Glutamyl-Transpeptidase-Resistant glutathione analog attenuates progression of Alzheimer’s disease-like pathology and neurodegeneration in a mouse model. Antioxidants, 10(11), 1796. https://doi.org/10.3390/antiox10111796.
47. Sweeney, M. D., Sagare, A. P., & Zlokovic, B. V. (2018). Blood-brain barrier breakdown in Alzheimer's disease and other neurodegenerative disorders. Nature Reviews. Neurology, 14(3), 133–150. https://doi.org/10.1038/nrneurol.2017.188
48. Zhang, Q., Yang, G., Luo, Y., Jiang, L., Chi, H., & Tian, G. (2024). Neuroinflammation in Alzheimer's disease: insights from peripheral immune cells. Immunity & ageing: I & A, 21(1), 38. https://doi.org/10.1186/s12979-024-00445-0
49. Takeda, S., Sato, N., & Morishita, R. (2014). Systemic inflammation, blood-brain barrier vulnerability, and cognitive/non-cognitive symptoms in Alzheimer's disease: relevance to pathogenesis and therapy. Frontiers in aging neuroscience, 6, 171. https://doi.org/10.3389/fnagi.2014.00171
50. Salter, M., Stevens, B. Microglia emerge as central players in brain disease. Nat Med 23, 1018–1027 (2017). https://doi.org/10.1038/nm.4397.
51. Wang, Y., Lin, Y., Wang, L., Zhan, H., Luo, X., Zeng, Y., Wu, W., Zhang, X., & Wang, F. (2020). TREM2 ameliorates neuroinflammatory response and cognitive impairment via PI3K/AKT/FoxO3a signaling pathway in Alzheimer’ s disease mice. Aging, 12(20), 20862–20879. https://doi.org/10.18632/aging.104104.
52. Maurya, S. K., Bhattacharya, N., Mishra, S., Bhattacharya, A., Banerjee, P., Senapati, S., & Mishra, R. (2021). Microglia Specific Drug Targeting Using Natural Products for the Regulation of Redox Imbalance in Neurodegeneration. Frontiers in pharmacology, 12, 654489. https://doi.org/10.3389/fphar.2021.654489
2. Al-Ghraiybah, N. F., Wang, J., Alkhalifa, A. E., Roberts, A. B., Raj, R., Yang, E., & Kaddoumi, A. (2022). Glial Cell-Mediated Neuroinflammation in Alzheimer's Disease. International journal of molecular sciences, 23(18), 10572. https://doi.org/10.3390/ijms231810572
3. Holtzman, D. M., Morris, J. C., & Goate, A. M. (2011). Alzheimer's disease: the challenge of the second century. Science translational medicine, 3(77), 77sr1. https://doi.org/10.1126/scitranslmed.3002369
4. Perl D. P. (2010). Neuropathology of Alzheimer's disease. The Mount Sinai journal of medicine, New York, 77(1), 32–42. https://doi.org/10.1002/msj.20157.
5. Choi, S. B., Kwon, S., Kim, J. H., Ahn, N. H., Lee, J. H., & Yang, S. H. (2023). The Molecular Mechanisms of Neuroinflammation in Alzheimer's Disease: The Consequence of Neural Cell Death. International journal of molecular sciences, 24(14), 11757. https://doi.org/10.3390/ijms241411757
6. Kwon, H. S., & Koh, S. H. (2020). Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Translational neurodegeneration, 9(1), 42. https://doi.org/10.1186/s40035-020-00221-2.
7. Leng, F., Edison, P. Neuroinflammation and microglial activation in Alzheimer's disease: where do we go from here? Nat Rev Neurol 17, 157–172 (2021). https://doi.org/10.1038/s41582-020-00435-y
8. Hong, S., Beja-Glasser, V. F., Nfonoyim, B. M., Frouin, A., Li, S., Ramakrishnan, S., ... & Stevens, B. (2016). Complement and microglia mediate early synapse loss in Alzheimer's mouse models. Science, 352(6286), 712–716. https://doi.org/10.1126/science.aad8373.
9. Gomez-Arboledas, A., Acharya, M. M., & Tenner, A. J. (2021). The Role of Complement in Synaptic Pruning and Neurodegeneration. ImmunoTargets and therapy, 10, 373–386. https://doi.org/10.2147/ITT.S305420
10. Liang, T., Zhang, Y., Wu, S., Chen, Q., & Wang, L. (2022). The Role of NLRP3 Inflammasome in Alzheimer's Disease and Potential Therapeutic Targets. Frontiers in pharmacology, 13, 845185. https://doi.org/10.3389/fphar.2022.845185
11. Ittner, L., Götz, J. Amyloid-β and tau — a toxic pas de deux in Alzheimer's disease. Nat Rev Neurosci 12, 67–72 (2011). https://doi.org/10.1038/nrn2967.
12. Haass, C., Selkoe, D. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide. Nat Rev Mol Cell Biol 8, 101–112 (2007). https://doi.org/10.1038/nrm2101.
13. Shimizu, H., Tosaki, A., Kaneko, K., Hisano, T., Sakurai, T., & Nukina, N. (2008). Crystal structure of an active form of BACE1, an enzyme responsible for amyloid beta protein production. Molecular and cellular biology, 28(11), 3663–3671. https://doi.org/10.1128/MCB.02185-07.
14. Haass, C., Lemere, C. A., Capell, A., Citron, M., Seubert, P., Schenk, D., Lannfelt, L., & Selkoe, D. J. (1995). The Swedish mutation causes early-onset Alzheimer's disease by beta-secretase cleavage within the secretory pathway. Nature medicine, 1(12), 1291–1296. https://doi.org/10.1038/nm1295-1291.
15. Weggen, S., & Beher, D. (2012). Molecular consequences of amyloid precursor protein and presenilin mutations causing autosomal-dominant Alzheimer's disease. Alzheimer's research & therapy, 4(2), 9. https://doi.org/10.1186/alzrt107.
16. Zhang, S., Wang, Z., Cai, F., Zhang, M., Wu, Y., Zhang, J., & Song, W. (2017). BACE1 Cleavage Site Selection Critical for Amyloidogenesis and Alzheimer's Pathogenesis. The Journal of neuroscience: the official journal of the Society for Neuroscience, 37(29), 6915–6925. https://doi.org/10.1523/JNEUROSCI.0340-17.2017.
17. Cole, S. L., & Vassar, R. (2007). The Alzheimer's disease beta-secretase enzyme, ACE1. Molecular neurodegeneration, 2, 22. https://doi.org/10.1186/1750-1326-2-22.
18. Zhang, X., & Song, W. (2013). The role of APP and BACE1 trafficking in APP processing and amyloid-β generation. Alzheimer's research & therapy, 5(5), 46. https://doi.org/10.1186/alzrt211.
19. Selkoe, D.J., Hardy, J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med 8, 595–608 (2016). https://doi.org/10.15252/emmm.201606210.
20. Palop, J., Mucke, L. Amyloid-β–induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks. Nat Neurosci 13, 812–818 (2010). https://doi.org/10.1038/nn.2583.
21. Shankar, G., Li, S., Mehta, T. et al. Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 14, 837–842 (2008). https://doi.org/10.1038/nm1782.
22. Heneka, M. T., Carson, M. J., Khoury, J. E., Landreth, G. E., Brosseron, F., Feinstein, D. L., Jacobs, A. H., Wyss-Coray, T., Vitorica, J., Ransohoff, R. M., Herrup, K., Frautschy, S. A., Finsen, B., Brown, G. C., Verkhratsky, A., Yamanaka, K., Koistinaho, J., Latz, E., Halle, A., . Kummer, M. P. (2015). Neuroinflammation in Alzheimer’s disease. The Lancet Neurology, 14(4), 388–405. https://doi.org/10.1016/s1474-4422(15)70016-5
23. Ulland, T. K., Song, W. M., & Colonna, M. (2017). TREM2 function in Alzheimer’s disease and neurodegeneration. ACS Chemical Neuroscience, 8(4), 809–818. https://doi.org/10.1021/acschemneuro.7b00063.
24. Trejo-Lopez, J. A., Yachnis, A. T., & Prokop, S. (2022). Neuropathology of Alzheimer's Disease. Neurotherapeutics: the journal of the American Society for Experimental NeuroTherapeutics, 19(1), 173–185. https://doi.org/10.1007/s13311-021-01146-y
25. Wang, Y., Mandelkow, E. Tau in physiology and pathology. Nat Rev Neurosci 17, 22–35 (2016). https://doi.org/10.1038/nrn.2015.1.
26. Clavaguera, F., Bolmont, T., Crowther, R. A., Abramowski, D., Frank, S., Probst, A., Fraser, G., Stalder, A. K., Beibel, M., Staufenbiel, M., Jucker, M., Goedert, M., & Tolnay, M. (2009). Transmission and spreading of tauopathy in transgenic mouse brain. Nature Cell Biology, 11(7), 909–913. https://doi.org/10.1038/ncb1901.
27. Goedert, M., Spillantini, M.G. Propagation of Tau aggregates. Mol Brain 10, 18 (2017). https://doi.org/10.1186/s13041-017-0298-7.
28. Pooler, A. M., Phillips, E. C., Lau, D. H., Noble, W., & Hanger, D. P. (2013). Physiological release of endogenous tau is stimulated by neuronal activity. EMBO reports, 14(4), 389–394. https://doi.org/10.1038/embor.2013.15.
29. Cummings, J., Lee, G., Zhong, K., Fonseca, J., & Taghva, K. (2021). Alzheimer's disease drug development pipeline: 2021. Alzheimer's & dementia (New York, N. Y.), 7(1), e12179. https://doi.org/10.1002/trc2.12179.
30. Panza, F., Lozupone, M., Logroscino, G., & Imbimbo, B. P. (2019). A critical appraisal of amyloid-β-targeting therapies for Alzheimer's disease. Nature Reviews. Neurology, 15(2), 73–88. https://doi.org/10.1038/s41582-018-0116-6.
31. Heneka, M. T., Golenbock, D. T., & Latz, E. (2015). Innate immunity in Alzheimer's disease. Nature immunology, 16(3), 229–236. https://doi.org/10.1038/ni.3102.
32. Salter, M., Stevens, B. Microglia emerge as central players in brain disease. Nat Med 23, 1018–1027 (2017). https://doi.org/10.1038/nm.4397.
33. Hansen, D. V., Hanson, J. E., & Sheng, M. (2017). Microglia in Alzheimer’s disease. The Journal of Cell Biology, 217(2), 459–472. https://doi.org/10.1083/jcb.201709069.
34. Basha, S. C., Ramaiah, M. J., & Kosagisharaf, J. R. (2023). Untangling the Role of TREM2 in Conjugation with Microglia in Neuronal Dysfunction: A Hypothesis on a Novel Pathway in the Pathophysiology of Alzheimer's Disease. Journal of Alzheimer's disease: JAD, 94(s1), S319–S333. https://doi.org/10.3233/JAD-221070
35. Dar, N. J., Bhat, J. A., John, U., & Bhat, S. A. (2024). Neuroglia in Neurodegeneration: Exploring Glial Dynamics in Brain Disorders. Neuroglia, 5(4), 488-504. https://doi.org/10.3390/neuroglia5040031.
36. Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., Ulland, T. K., David, E., Baruch, K., Lara-Astaiso, D., Toth, B., Itzkovitz, S., Colonna, M., Schwartz, M., & Amit, I. (2017). A Unique Microglia Type Associated with Restricting the Development of qAlzheimer's Disease. Cell, 169(7), 1276–1290.e17. https://doi.org/10.1016/j.cell.2017.05.018.
37. Wang, S., Mustafa, M., Yuede, C. M., Salazar, S. V., Kong, P., Long, H., Ward, M., Siddiqui, O., Paul, R., Gilfillan, S., Ibrahim, A., Rhinn, H., Tassi, I., Rosenthal, A., Schwabe, T., & Colonna, M. (2020). Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model. The Journal of Experimental Medicine, 217(9). https://doi.org/10.1084/jem.20200785.
38. Heneka, M. T., Kummer, M. P., Stutz, A., Delekate, A., Schwartz, S., Vieira-Saecker, A., Griep, A., Axt, D., Remus, A., Tzeng, T. C., Gelpi, E., Halle, A., Korte, M., Latz, E., & Golenbock, D. T. (2013). NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature, 493(7434), 674–678. https://doi.org/10.1038/nature11729.
39. Yin, J., Zhao, F., Chojnacki, J. E., Fulp, J., Klein, W. L., Zhang, S., & Zhu, X. (2018). NLRP3 Inflammasome Inhibitor Ameliorates Amyloid Pathology in a Mouse Model of Alzheimer's Disease. Molecular neurobiology, 55(3), 1977–1987. https://doi.org/10.1007/s12035-017-0467-9.
40. Cornell, J., Salinas, S., Huang, H. Y., & Zhou, M. (2022). Microglia regulation of synaptic plasticity, learning, and memory. Neural regeneration research, 17(4), 705–716. https://doi.org/10.4103/1673-5374.322423
41. Hamelin, L., Lagarde, J., Dorothée, G., Leroy, C., Labit, M., Comley, R. A., de Souza, L. C., Corne, H., Dauphinot, L., Bertoux, M., Dubois, B., Gervais, P., Colliot, O., Potier, M. C., Bottlaender, M., Sarazin, M., & Clinical IMABio3 team (2016). Early and protective microglial activation in Alzheimer's disease: a prospective study using 18F-DPA-714 PET imaging. Brain: a journal of neurology, 139(Pt 4), 1252–1264. https://doi.org/10.1093/brain/aww017.
42. Rauchmann, B. S., Brendel, M., Franzmeier, N., Trappmann, L., Zaganjori, M., Ersoezlue, E., Morenas-Rodriguez, E., Guersel, S., Burow, L., Kurz, C., Haeckert, J., Tatò, M., Utecht, J., Papazov, B., Pogarell, O., Janowitz, D., Buerger, K., Ewers, M., Palleis, C., Weidinger, E., Perneczky, R. (2022). Microglial Activation and Connectivity in Alzheimer's Disease and Aging. Annals of Neurology, 92(5), 768–781. https://doi.org/10.1002/ana.26465.
43. Wang, Q., Chen, G., Schindler, S. E., Christensen, J., McKay, N. S., Liu, J., Wang, S., Sun, Z., Hassenstab, J., Su, Y., Flores, S., Hornbeck, R., Cash, L., Cruchaga, C., Fagan, A. M., Tu, Z., Morris, J. C., Mintun, M. A., Wang, Y., & Benzinger, T. L. S. (2022). Baseline Microglial Activation Correlates with Brain Amyloidosis and Longitudinal Cognitive Decline in Alzheimer Disease. Neurology(R) neuroimmunology & neuroinflammation, 9(3), e1152. https://doi.org/10.1212/NXI.0000000000001152.
44. Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W. S., Peterson, T. C., Wilton, D. K., Frouin, A., Napier, B. A., Panicker, N., Kumar, M., Buckwalter, M. S., Rowitch, D. H., Dawson, V. L., Dawson, T. M., Stevens, B., Barres, B. A. (2017). Neurotoxic reactive astrocytes are induced by activated microglia. Nature, 541(7638), 481–487. https://doi.org/10.1038/nature21029
45. Oksanen, M., Hyötyläinen, I., Trontti, K., Rolova, T., Wojciechowski, S., Koskuvi, M., Viitanen, M., Levonen, A. L., Hovatta, I., Roybon, L., Lehtonen, Š., Kanninen, K. M., Hämäläinen, R. H., & Koistinaho, J. (2020). NF-E2-related factor 2 activation boosts antioxidant defenses and ameliorates inflammatory and amyloid properties in human Presenilin-1 mutated Alzheimer's disease astrocytes. Glia, 68(3), 589–599. https://doi.org/10.1002/glia.23741.
46. Kwon, Y. I. C., Xie, W., Zhu, H., Xie, J., Shinn, K., Juckel, N., Vince, R., More, S. S., & Lee, M. K. (2021). Γ-Glutamyl-Transpeptidase-Resistant glutathione analog attenuates progression of Alzheimer’s disease-like pathology and neurodegeneration in a mouse model. Antioxidants, 10(11), 1796. https://doi.org/10.3390/antiox10111796.
47. Sweeney, M. D., Sagare, A. P., & Zlokovic, B. V. (2018). Blood-brain barrier breakdown in Alzheimer's disease and other neurodegenerative disorders. Nature Reviews. Neurology, 14(3), 133–150. https://doi.org/10.1038/nrneurol.2017.188
48. Zhang, Q., Yang, G., Luo, Y., Jiang, L., Chi, H., & Tian, G. (2024). Neuroinflammation in Alzheimer's disease: insights from peripheral immune cells. Immunity & ageing: I & A, 21(1), 38. https://doi.org/10.1186/s12979-024-00445-0
49. Takeda, S., Sato, N., & Morishita, R. (2014). Systemic inflammation, blood-brain barrier vulnerability, and cognitive/non-cognitive symptoms in Alzheimer's disease: relevance to pathogenesis and therapy. Frontiers in aging neuroscience, 6, 171. https://doi.org/10.3389/fnagi.2014.00171
50. Salter, M., Stevens, B. Microglia emerge as central players in brain disease. Nat Med 23, 1018–1027 (2017). https://doi.org/10.1038/nm.4397.
51. Wang, Y., Lin, Y., Wang, L., Zhan, H., Luo, X., Zeng, Y., Wu, W., Zhang, X., & Wang, F. (2020). TREM2 ameliorates neuroinflammatory response and cognitive impairment via PI3K/AKT/FoxO3a signaling pathway in Alzheimer’ s disease mice. Aging, 12(20), 20862–20879. https://doi.org/10.18632/aging.104104.
52. Maurya, S. K., Bhattacharya, N., Mishra, S., Bhattacharya, A., Banerjee, P., Senapati, S., & Mishra, R. (2021). Microglia Specific Drug Targeting Using Natural Products for the Regulation of Redox Imbalance in Neurodegeneration. Frontiers in pharmacology, 12, 654489. https://doi.org/10.3389/fphar.2021.654489