The p300-NF-κB pathway induces the activation of the NLRP3 inflammasome and the pyroptosis of neurons in an in vitro model of Alzheimer’s disease.
En el modelo in vitro de la enfermedad de Alzheimer, la vía p300 NF - Kappa B induce la activación del inflamasoma NLRP3 y la piroptosis neuronal en un modelo in vitro de la enfermedad de Alzheimer.
Keywords:
Alzheimer’s disease, p300, pyroptosis, NLRP3 inflammasome
Abstract
Inflammation-induced neuronal death is the primary cause of Alzheimer’s disease (AD). p300 plays an important role in brain disorders. However, the role of p300 in AD remains unclear. This study aimed to investigate the potential of p300 in an in vitro model of AD. Protein expression was detected using western blotting. The mRNA levels were determined by reverse transcrip- tion-quantitative polymerase chain reaction. Cytokine release was detected using an enzyme-linked immunosorbent assay. Cellular function was determined using the cell counting kit-8, lactate dehydrogenase, and flow cytometry assays. Chromatin immunoprecipitation and luciferase assays verified the interaction between nuclear factor kappa B (NF-κB) and the NLR family pyrin domain con- taining 3 (NLRP3). E1A binding protein p300 (p300) was overexpressed in the Aβ 1-42 induced AD model in vitro. However, treatment with the p300 inhibitor (GNE-049) alleviated inflammation and Aβ 1-42-induced pyroptosis in the neurons. p300 activates NF-κB, which antagonizes the effects of GNE-049 and pro- motes neuronal pyroptosis. Moreover, NF-κB epigenetically activates the NLRP3 inflammasome. The p300/NF-κB pathway promotes neuronal pyroptosis in an in vitro AD model by activating the NLRP3 inflammasome. Therefore, the p300/ NF-κB/NLRP3 signalling pathway may be a potential therapeutic target for AD.
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References
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Porsteinsson AP, Isaacson RS, Knox S, Sabbagh MN, Rubino I. Diagnosis of Early Alzheimer’s Disease: Clinical Practice in 2021. J Prev Alzheimers Dis. 2021;8(3):371-86. doi: https://doi.org/10.14283/jpad.2021.23.
2023 Alzheimer’s disease facts and figures. Alzheimers Dement. 2023;19(4):1598- 695. doi: https://doi.org/10.1002/alz.13016.
Graff-Radford J, Yong KXX, Apostolova LG, Bouwman FH, Carrillo M, Dickerson BC, et al. New insights into atypical Alzheimer’s disease in the era of biomarkers. Lancet Neurol. 2021;20(3):222-34. doi: https://doi.org/10.1016/S1474-4422(20)30440-3.
Wang Q, Gao F, Dai LN, Zhang J, Bi D, Shen Y. Clinical Research Investigating Alzheimer’s Disease in China: Current Status and Future Perspectives Toward Prevention. J Prev Alzheimers Dis. 2022;9(3):532-41. doi: https://doi.org/10.14283/jpad.2022.46.
Fan R, Peng X, Xie L, Dong K, Ma D, Xu W, et al. Importance of Bmal1 in Alzheimer’s disease and associated aging-related diseases: Mechanisms and interventions. Aging Cell. 2022;21(10):e13704. doi: https://doi.org/10.1111/acel.13704.
Chen P, Guo Z, Zhou B. Insight into the role of adult hippocampal neurogenesis in aging and Alzheimer’s disease. Ageing Res Rev. 2023;84:101828. doi: https://doi.org/10.1016/j. arr.2022.101828.
Yang F, Bettadapura SN, Smeltzer MS, Zhu H, Wang S. Pyroptosis and pyroptosis inducing cancer drugs. Acta Pharmacol Sin. 2022;43(10):2462-73. doi: https://doi.org/10.1038/s41401-022-00887-6.
Moonen S, Koper MJ, Van Schoor E, Schaeverbeke JM, Vandenberghe R, von Arnim CAF, et al. Pyroptosis in Alzheimer’s disease: cell type-specific activation in microglia, astrocytes and neurons. Acta Neuropathol. 2023;145(2):175-95. doi: https://doi.org/10.1007/s00401-022-02528-y.
Zhou J, Qiu J, Song Y, Liang T, Liu S, Ren C, et al. Pyroptosis and degenerative diseases of the elderly. Cell Death Dis. 2023;14(2):94. doi: https://doi.org/10.1038/s41419-023-05634-1.
Elias EE, Lyons B, Muruve DA. Gasdermins and pyroptosis in the kidney. Nat Rev Nephrol. 2023;19(5):337-50. doi: https://doi.org/10.1038/s41581-022-00662-0.
Li Z, Ji S, Jiang ML, Xu Y, Zhang CJ. The Regulation and Modification of GSD-MD Signaling in Diseases. Front Immunol. 2022;13:893912. doi: https://doi.org/10.3389/fimmu.2022.893912.
Huang Y, Xu W, Zhou R. NLRP3 inflammasome activation and cell death. Cell Mol Immunol. 2021;18(9):2114-27. doi: https://doi.org/10.1038/s41423-021-00740-6.
Yao H, Zhang D, Yu H, Yuan H, Shen H, Lan X, et al. Gut microbiota regulates chronic ethanol exposure-induced depressive-like behavior through hippocampal NLRP3-mediated neuroinflammation. Mol Psychiatry. 2023;28(2):919-30. doi: https://doi.org/10.1038/s41380-022-01841-y.
Hou Y, Wei Y, Lautrup S, Yang B, Wang Y, Cordonnier S, et al. NAD(+) supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer’s disease via cGAS-STING. Proc Natl Acad Sci U S A. 2021;118(37). doi: https://doi.org/10.1073/pnas.2011226118.
Han YH, Liu XD, Jin MH, Sun HN, Kwon T. Role of NLRP3 inflammasome- mediated neuronal pyroptosis and neuroinflammation in neurodegenerative diseases. Inflamm Res. 2023;72(9):1839-59. doi: https://doi.org/10.1007/s00011-023-01790-4.
Cai Y, Chai Y, Fu Y, Wang Y, Zhang Y, Zhang X, et al. Salidroside Ameliorates Alzheimer’s Disease by Targeting NLRP3 Inflammasome-Mediated Pyroptosis. Front Aging Neurosci. 2021;13:809433. doi: https://doi.org/10.3389/fnagi.2021.809433.
Chakraborty R, Ostriker AC, Xie Y, Dave JM, Gamez-Mendez A, Chatterjee P, et al. Histone Acetyltransferases p300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle Plasticity. Circulation. 2022;145(23):1720-37. doi: https://doi.org/10.1161/CIRCULATIONAHA.121.057599.
Xu Y, Wan W. Acetylation in the regulation of autophagy. Autophagy. 2023;19(2):379-87. doi: https://doi.org/10.1080/15548627.2022.2062112.
Chen Q, Yang B, Liu X, Zhang XD, Zhang L, Liu T. Histone acetyltransferases CBP/ p300 in tumorigenesis and CBP/p300 inhibitors as promising novel anticancer agents. Theranostics. 2022;12(11):4935-48. doi: https://doi.org/10.7150/thno.73223.
Cao W, Feng Z, Zhu D, Li S, Du M, Ye S, et al. The Role of PGK1 in Promoting Ischemia/Reperfusion Injury-Induced Microglial M1 Polarization and Inflammation by Regulating Glycolysis. Neuromolecular Med. 2023;25(2):301-11. doi: https://doi.org/10.1007/s12017-023-08736-3.
Bai B, Zhang Q, Wan C, Li D, Zhang T, Li H. CBP/p300 inhibitor C646 prevents high glucose exposure induced neuroepithelial cell proliferation. Birth Defects Res. 2018;110(14):1118-28. doi: https://doi.org/10.1002/bdr2.1360.
Cintra MTG, Avila RT, Soares TO, Cunha LCM, Silveira KD, de Moraes EN, et al. Increased N200 and P300 latencies in cognitively impaired elderly carrying ApoE epsilon-4 allele. Int J Geriatr Psychiatry. 2018;33(2):e221-e7. doi: https://doi.org/10.1002/gps.4773.
Chatterjee S, Mizar P, Cassel R, Neidl R, Selvi BR, Mohankrishna DV, et al. A novel activator of CBP/p300 acetyltransferases promotes neurogenesis and extends memory duration in adult mice. J Neurosci. 2013;33(26):10698-712. doi: https://doi.org/10.1523/JNEUROSCI.5772-12.2013.
Chen X, Li Y, Wang C, Tang Y, Mok SA, Tsai RM, et al. Promoting tau secretion and propagation by hyperactive p300/CBP via autophagy-lysosomal pathway in tauopathy. Mol Neurodegener. 2020;15(1):2. doi: https://doi.org/10.1186/s13024-019-0354-0.
Shin MK, Vazquez-Rosa E, Koh Y, Dhar M, Chaubey K, Cintron-Perez CJ, et al. Reducing acetylated tau is neuroprotective in brain injury. Cell. 2021;184(10):2715-32 e23. doi: https://doi.org/10.1016/j.cell.2021.03.032.
Wu J, Han Y, Xu H, Sun H, Wang R, Ren H, et al. Deficient chaperone-mediated autophagy facilitates LPS-induced microglial activation via regulation of the p300/NF-kappaB/NLRP3 pathway. Sci Adv. 2023;9(40):eadi8343. doi: https://doi.org/10.1126/sciadv.adi8343.
Kikuchi M, Morita S, Wakamori M, Sato S, Uchikubo-Kamo T, Suzuki T, et al. Epigenetic mechanisms to propagate histone acetylation by p300/CBP. Nat Commun. 2023;14(1):4103. doi: https://doi.org/10.1038/s41467-023-39735-4.
Takouda J, Katada S, Imamura T, Sanosaka T, Nakashima K. SoxE group transcription factor Sox8 promotes astrocytic differentiation of neural stem/precursor cells downstream of Nfia. Pharmacol Res Perspect. 2021;9(6):e00749. doi: https://doi.org/10.1002/prp2.749.
Pajarillo E, Digman A, Nyarko-Danquah I, Son DS, Soliman KFA, Aschner M, et al. Astrocytic transcription factor REST upregulates glutamate transporter EAAT2, protecting dopaminergic neurons from manganese-induced excitotoxicity. J Biol Chem. 2021;297(6):101372. doi: https://doi.org/10.1016/j.jbc.2021.101372.
Jeong GW, Lee HH, Lee-Kwon W, Kwon HM. Microglial TonEBP mediates LPS- induced inflammation and memory loss as transcriptional cofactor for NF-kappaB and AP-1. J Neuroinflammation. 2020;17(1):372. doi: https://doi.org/10.1186/s12974-020-02007-9.
Chen S, Liu H, Wang S, Jiang H, Gao L, Wang L, et al. The Neuroprotection of Verbascoside in Alzheimer’s Disease Mediated through Mitigation of Neuroinflammation via Blocking NF-kappaB-p65 Signaling. Nutrients. 2022;14(7). doi: https://doi.org/10.3390/nu14071417.
Zhou L, Kong G, Palmisano I, Cencioni MT, Danzi M, De Virgiliis F, et al. Reversible CD8 T cell-neuron cross-talk causes aging-dependent neuronal regenerative decline. Science. 2022;376(6594):eabd5926. doi: https://doi.org/10.1126/science.abd5926.
Yu CH, Davidson S, Harapas CR, Hilton JB, Mlodzianoski MJ, Laohamonthonkul P, et al. TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/ STING in ALS. Cell. 2020;183(3):636-49 e18. doi: https://doi.org/10.1016/j.cell.2020.09.020.
Jung BK, Park Y, Yoon B, Bae JS, Han SW, Heo JE, et al. Reduced secretion of LCN2 (lipocalin 2) from reactive astrocytes through autophagic and proteasomal regulation alleviates inflammatory stress and neuronal damage. Autophagy. 2023;19(8):2296-317. doi: https://doi.org/10.1080/15548627.2023.2180202.
Chen S, Guan S, Yan Z, Ouyang F, Li S, Liu L, et al. Role of RIPK3‑CaMKII‑mPTP signaling pathway‑mediated necroptosis in cardiovascular diseases (Review). Int J Mol Med. 2023;52(4). doi: https://doi.org/10.3892/ ijmm.2023.5301.
Frank D, Vince JE. Pyroptosis versus necroptosis: similarities, differences, and crosstalk. Cell Death Differ. 2019;26(1):99-114. doi: https://doi.org/10.1038/s41418-018-0212-6.
Gao W, Wang X, Zhou Y, Wang X, Yu Y. Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy. Signal Transduct Target Ther. 2022;7(1):196. doi: https://doi.org/10.1038/s41392-022-01046-3.
Published
2025-06-06
How to Cite
Sun, F., & Huang, W. (2025). The p300-NF-κB pathway induces the activation of the NLRP3 inflammasome and the pyroptosis of neurons in an in vitro model of Alzheimer’s disease.: En el modelo in vitro de la enfermedad de Alzheimer, la vía p300 NF - Kappa B induce la activación del inflamasoma NLRP3 y la piroptosis neuronal en un modelo in vitro de la enfermedad de Alzheimer. Investigación Clínica, 66(2), 191-204. https://doi.org/10.54817/IC.v66n2a06
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