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Role of inhibiting lncRNA TUG1 to down-regulate nucleotide binding oligomerization domain like receptor protein 1 inflammasome in delaying the progression of Alzheimer’s disease
MA Ting-ting CHEN Jian-hong LIU Ai-cui LI Hai-ning
Acta Anatomica Sinica ›› 2024, Vol. 55 ›› Issue (1) : 32-42.
PDF(3561 KB)
PDF(3561 KB)
Role of inhibiting lncRNA TUG1 to down-regulate nucleotide binding oligomerization domain like receptor protein 1 inflammasome in delaying the progression of Alzheimer’s disease
MA Ting-ting CHEN Jian-hong LIU Ai-cui LI Hai-ning*
Objective To investigate the relieving effects of knockdown of long non-coding RNA（lncRNA）taurine up-regulated gene 1 (TUG1) on inhibiting nucleotide binding oligomerization domain like receptor protein 1(NLRP1) inflammasome and the progression of Alzheimer’s disease. Methods Wild-type (WT group,10 mice) or amyloid precursor protein (APP)/presenilin-1 (PS1) transgenic mice (30 mice) with a genetic background of C57/BL6 aged 9-10 weeks were used in this study. APP/PS1 transgenic mice were randomly divided into model group, model+lncRNA TUG1 short hairpin RNA (shRNA) group and model+shRNA non target（NT）group (n=10). Blood samples, cerebral cortex tissues, primary microglial cells and primary astrocytes were collected from mice 12 weeks of age on day 1 (3-month-old) and 32 weeks of age on day 1 (8-month-old), with 5 mice per group at each time point. Real-time PCR analysis was used to detect the expression levels of lncRNA TUG1 and macrophage migration inhibitory factor (MIF) mRNA in cerebral cortex tissues and primary microglial cells, and C1r and C1s mRNA levels in primary astrocytes of 3-month-old and 8-month-old mice in the above 4 groups, respectively. ELISA was used to determine the MIF in plasma samples of the above 4 groups of mice. Primary microglia and astrocytes from the cerebral cortex of 3-month-old and 8-month-old mice were co-cultured. CCK-8 method was used to determine the proliferation ability of the above cells. Western blotting was used to determine the expression levels of MIF, pro interleukin-1β(pro-IL-1β), apoptosis associated speck-like protein containing a caspase recrult domain(ASC), Caspase-1 (p20), Caspase-1 (full), NLRP1 and NLRP3 in cerebral cortex tissues of 3-month-old and 8-month-old mice. Immunofluorescent staining was used to determine amyloid beta（Aβ）in cerebral cortex of 8-month-old mice. Results At the age of 3-month-old and 8-month-old, compared with the WT group, the relative expression level of lncRNA TUG1 and MIF in cerebral cortex tissues and primary microglia of model group mice was significantly up-regulated, with primary microglial cells and astrocytes proliferation ability enhanced (P<0.05). Compared with the model group, the relative expression level of lncRNA TUG1 and MIF cerebral cortex tissues and primary microglia of model+lncRNA TUG1 shRNA group were significantly down-regulated, with primary microglial cells and astrocytes proliferation ability decreased (P<0.05). Compared with the WT group, MIF factor in the peripheral plasma of model group increased significantly, with pro-IL-1β，ASC，Caspase-1 (p20)，Caspase-1 (full), NLRP1 and NLRP3 expression level up-regulated in the model group mice cerebral cortex tissues, with increased Aβ immunofluorescent indensity (P<0.05). Compared with the model group, MIF factor in the peripheral plasma, and pro-IL-1β，ASC，Caspase-1 (p20)，Caspase-1 (full) and NLRP1 expression in the model+lncRNA TUG1 shRNA group mice cerebral cortex tissues were down-regulated, and Aβ immunofluorescent indensity decreased (P<0.05), while NLRP3 expression level were not changed (P>0.05). There was no significant difference between the model group and the model+shRNA NT group mice of all the above factors (P>0.05). Conclusion In APP/PS1 transgenic mice, up-regulation of lncRNA TUG1 and MIF are positively associated with the activation of NLRP1 inflammasome in mice cerebral cortex tissues and primary microglia. Knock-down of lncRNA TUG1 can ameliorate the progression of Alzheimer’s disease.
Alzheimer’s disease
［1］Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer’s disease ［J］. Lancet, 2021, 397(10284):1577-1590.
［2］Zhang XX, Tian Y, Wang ZT, et al. The epidemiology of Alzhelmer’s disease modifiable risk factors and prevention［J］. J Prev Alzheimers DIs, 2021, 8(3):313-321.
［3］Soria Lopez JA, González HM, Léger GC. Alzheimer’s disease ［J］. Handb Clin Neuro, 2019, 167:231-255.
［4］Hansen DV, Hanson JE, Sheng M. Microglia in Alzheimer’s disease ［J］. J Cell Biol, 2018, 217(2):459-472.
［5］Long JM, Holtzman DM. Alzheimer disease: an update on pathobiology and treatment strategies ［J］. Cell, 2019, 179(2):312-339.
［6］Quinn JJ, Chang HY. Unique features of long non-coding RNA biogenesis and function ［J］. Nat Rev Genet, 2019, 17(1):47-62.
［7］Xu Y, Niu YL, Li HY, et al. Downregulation of lncRNA TUG1 attenuates inflammation and apoptosis of renal tubular epithelial cell induced by ischemia-reperfusion by sponging miR-449b-5p via targeting HMGB1 and MMP2 ［J］. Inflammation, 2020, 43(4):1362-1374.
［8］Ngwa C, Qi SH, Mamun AA, et al. Age and sex differences in primary microglia culture: a comparative study ［J］. J Neurosci Methods, 2021, 364:109359.
［9］Liddelow SA, Guttenplan KA, Clarke LE, et al. Neurotoxic reactive astrocytes are induced by activated microglia ［J］. Nature, 2017, 541(7638):481-487.
［10］Ofengeim D, Mazzitelli S, Ito Y, et al. RIPK1 mediates a disease-associated microglial response in Alzheimer’s disease ［J］. PNAS, 2017, 114(41):E8788-E8797.
［11］Novoa C, Salazar P, Cisternas P, et al. Inflammation context in Alzheimer’s disease, a relationship intricate to define ［J］. Biol Res, 2022, 55(1):39.
［12］Hou J, Chen Y, Grajales-Reyes G, et al. TREM2 dependent and independent functions of microglia in Alzheimer’s disease ［J］. Mol Neurodegener, 2022, 17(1):84.
［13］Bhattacharyya N, Pandey V, Bhattacharyya M, et al. Regulatory role of long non coding RNAs (lncRNAs) in neurological disorders: from novel biomarkers to promising therapeutic strategies ［J］. Asian J Pharm Sci, 2021, 16(5):533-550.
［14］Yao ML, Luo Y, Li HJ, et al. LncRNA Tug1 contributes post-stroke NLRP3 inflammasome-dependent pyroptosis via miR-145a-5p/Tlr4 axis ［J］. Mol Neurobiol, 2022, 59(11):6701-6712.
［15］Cheng J, Duan Y, Zhang F, et al. The role of lncRNA TUG1 in the Parkinson disease and its effect on microglial inflammatory response ［J］. Neuromolecular Med, 2021, 23(2):327-334.
［16］Xue LX, Chen SF, Xue SX, et al. LncRNA TUG1 compromised neuronal mitophagy in cerebral ischemia/reperfusion injury by targeting sirtuin 1 ［J］. Cell Biol Toxicol, 2022, 38(6):1121-1136.
［17］Yang B, Liang RS, Wu XY, et al. LncRNA TUG1 inhibits neuronal apoptosis in status epilepticus rats via targeting the miR-421/mTOR axis ［J］. Cell Signal, 2020, 76:109787.
［18］Djordjevic A, Bursa B, Veli?kovi? N, et al. Disturbances of systemic and hippocampal insulin sensitivity in macrophage migration inhibitory factor (MIF) knockout male mice lead to behavioral changes associated with decreased PSA-NCAM levels ［J］. Horm Behav, 2017, 96:95-103.
［19］Rao AVS, Choi Y, Aggarwal A, et al. PAAN/MIF nuclease inhibition prevents neurodegeneration in Parkinson’s disease ［J］. Cell, 2022, 185(11):1943-1959.
［20］Hansen DV, Hanson JE, Sheng M. Microglia in Alzheimer’s disease ［J］. J Cell Biol, 2018, 217(2):459-472.
［21］Su X, Zhang Zh, Yang LJ, et al. Granulocyte colony stimulating factor improving the learning and memory function and its anti-inflammatory mechanism of Alzheimer’s disease model rats ［J］. Acta Anatomica Sinica, 2019, 50(1):29-34.(in Chinese)
苏翔,张臻,杨霖璟,等.粒细胞集落刺激因子改善阿尔茨海默病模型大鼠学习记忆功能及抗炎作用机制［J］.解剖学报,2019,50(1):29-34.
［22］Yin J, Zhao FP, Chojnacki JE, et al. NLRP3 inflammasome inhibitor ameliorates amyloid pathology in a mouse model of Alzheimer’s disease ［J］. Mol Neurobiol, 2018, 55(3):1977-1987.
［23］Lang WY, Zhang ChM, Zhang YD, et al. Anti-oxidative stress mechanism of velvet antler polypeptide in Alzheimer’s disease model mice ［J］. Acta Anatomica Sinica, 2022, 53(4):432-439. (in Chinese)
郎尉雅,张春梅,张羽镝,等.鹿茸多肽在阿尔茨海默病模型小鼠中抗氧化应激的作用机制［J］.解剖学报,2022,53(4):432-439.
［24］Sun D, Gao G, Zhong B, et al. NLRP1 inflammasome involves in learning and memory impairments and neuronal damages during aging process in mice ［J］. Behav Brain Funct, 2021, 17(1):11.
［25］Li Q, Wang Q, Guan H, et al. Schisandrin inhibits NLRP1 inflammasome-mediated neuronal pyroptosis in mouse models of Alzheimer’s disease ［J］. Neuropsychiatr Dis Treat, 2021, 17:261-268.
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