Potential Regulatory Role of miR-21 on Alzheimer’s Disease by Targeting GSK-3β Signaling
DOI:
https://doi.org/10.31661/gmj.v12i.3027Keywords:
Alzheimer’s Disease, miR-21, PI3K/AKT/GSK-3β, ApoptosisAbstract
Background: Alzheimer’s disease (AD) is the most important neurogenerative disorder with progressive dementia as its main clinical manifestation. The microRNAs (miRNAs) are identified as crucial modulators in AD progression. Nevertheless, the biological potential of miR-21 in AD is obscure. Hence, this study aimed to evaluate the possible role of miR-21 in the pathogenesis of AD via phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/glycogen synthase kinase-3beta (GSK-3β) signaling. Materials and Methods: The miR-21 expression in the brain tissues of patients with AD, as well as normal brain tissues and Aβ1-42-stimulated SH-SY5Y cell line (AD model) was examined by in situ hybridization and quantitative real-time polymerase chain reaction. Also, the apoptosis-linked protein levels as well as programmed cell death 4 (PDCD4) were detected by western blot. Results: Our findings revealed that miR-21 was low expressed in the brain tissues of patients with AD and AD model (P<0.01). Also, the miR-21 overexpression could inhibit apoptosis of the AD model (P<0.01). Indeed, the miR-21 negatively regulated PDCD4 expression, which led to activated PI3K/AKT/GSK-3β signaling. Conclusion: Our study demonstrated that miR-21 cloud inhibits cell apoptosis in AD through the activation of PI3K/AKT/GSK-3β signaling pathway using inhibition of PDCD4 expression.
References
Choi SH, Kim YH, Hebisch M, Sliwinski C, Lee S, D'Avanzo C, et al. A three-dimensional human neural cell culture model of Alzheimer's disease. Nature. 2014; 515(7526): 274-8. https://doi.org/10.1038/nature13800PMid:25307057 PMCid:PMC4366007 Keogh-Brown MR, Jensen HT, Arrighi HM, Smith RD. The Impact of Alzheimer's Disease on the Chinese Economy. EBioMedicine. 2016; 4: 184-90. https://doi.org/10.1016/j.ebiom.2015.12.019PMid:26981556 PMCid:PMC4776062 Saiz-Sanchez D, De la Rosa-Prieto C, Ubeda-Banon I, Martinez-Marcos A. Interneurons, tau and amyloid-β in the piriform cortex in Alzheimer's disease. Brain Struct Funct. 2015;220(4):2011-25. https://doi.org/10.1007/s00429-014-0771-3PMid:24748561 Pamphlett R, Kum Jew S. Different Populations of Human Locus Ceruleus Neurons Contain Heavy Metals or Hyperphosphorylated Tau: Implications for Amyloid-β and Tau Pathology in Alzheimer's Disease. J Alzheimers Dis. 2015;45(2):437-47. https://doi.org/10.3233/JAD-142445PMid:25547633 Shafizadeh M, Jangholi E, Maroufi SF, Rostami M, Bereimipour A, Majidi S, et al. Effects of Dimethyl Fumarate on the Karnofsky Performance Status and Serum S100β Level in Newly Glioblastoma Patients: A Randomized, Phase-II, Placebo, Triple Blinded, Controlled Trial. Galen Med J. 2022;11: e1897. https://doi.org/10.31661/gmj.v11i.1897PMid:36340958 PMCid:PMC9616682 Chen ML, Hong CG, Yue T, Li HM, Duan R, Hu WB, et al. Inhibition of miR-331-3p and miR-9-5p ameliorates Alzheimer's disease by enhancing autophagy. Theranostics. 2021;11(5):2395-409. https://doi.org/10.7150/thno.47408PMid:33500732 PMCid:PMC7797673 Shi Z, Zhang K, Zhou H, Jiang L, Xie B, Wang R, et al. Increased miR-34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS-JNK-p53 pathway in Alzheimer's Disease. Aging Cell. 2020;19(3):e13125. https://doi.org/10.1111/acel.13125 Xue B, Qu Y, Zhang X, Xu XF. miRNA-126a-3p participates in hippocampal memory via alzheimer's disease-related proteins. Cereb Cortex. 2022;32(21):4763-81. https://doi.org/10.1093/cercor/bhab515PMid:35059720 Tang J, Li X, Cheng T, Wu J. miR-21-5p/SMAD7 axis promotes the progress of lung cancer. Thorac Cancer. 2021;12(17):2307-13. https://doi.org/10.1111/1759-7714.14060PMid:34254453 PMCid:PMC8410517 Yan H, Huang W, Rao J, Yuan J. miR-21 regulates ischemic neuronal injury via the p53/Bcl-2/Bax signaling pathway. Aging (Albany NY). 2021;13(18):22242-55. https://doi.org/10.18632/aging.203530PMid:34552038 PMCid:PMC8507259 Moshar S, Rezasoltani M, Namazi MJ. Angiographic examination in patients with Myocardial Infarction with and without ST segment elevation. Journal of Advanced Pharmacy Education & Research. 2020;10(S2):83-91. Montalban E, Mattugini N, Ciarapica R, Provenzano C, Savino M, Scagnoli F, et al. MiR-21 is an Ngf-modulated microRNA that supports Ngf signaling and regulates neuronal degeneration in PC12 cells. Neuromolecular Med. 2014;16(2):415-30. https://doi.org/10.1007/s12017-014-8292-zPMid:24492999 PMCid:PMC4019824 Chen S, Peng J, Sherchan P, Ma Y, Xiang S, Yan F, et al. TREM2 activation attenuates neuroinflammation and neuronal apoptosis via PI3K/Akt pathway after intracerebral hemorrhage in mice. J Neuroinflammation. 2020;17(1):168. https://doi.org/10.1186/s12974-020-01853-xPMid:32466767 PMCid:PMC7257134 Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K Pathway in Human Disease. Cell. 2017;170(4):605-35. https://doi.org/10.1016/j.cell.2017.07.029PMid:28802037 PMCid:PMC5726441 Porta C, Paglino C, Mosca A. Targeting PI3K/Akt/mTOR Signaling in Cancer. Front Oncol. 2014;4:64. https://doi.org/10.3389/fonc.2014.00064PMid:24782981 PMCid:PMC3995050 Xue R, Wan Y, Sun X, Zhang X, Gao W, Wu W. Nicotinic Mitigation of Neuroinflammation and Oxidative Stress After Chronic Sleep Deprivation. Front Immunol. 2019;10:2546. https://doi.org/10.3389/fimmu.2019.02546PMid:31736967 PMCid:PMC6828928 Liao S, Wu J, Liu R, Wang S, Luo J, Yang Y, et al. A novel compound DBZ ameliorates neuroinflammation in LPS-stimulated microglia and ischemic stroke rats: Role of Akt(Ser473)/GSK3β(Ser9)-mediated Nrf2 activation. Redox Biol. 2020;36:101644. https://doi.org/10.1016/j.redox.2020.101644PMid:32863210 PMCid:PMC7371982 Zhang Y, Huang NQ, Yan F, Jin H, Zhou SY, Shi JS, et al. Diabetes mellitus and Alzheimer's disease: GSK-3β as a potential link. Behav Brain Res. 2018;339:57-65. https://doi.org/10.1016/j.bbr.2017.11.015PMid:29158110 Woodgett JR. Recent advances in the protein kinase B signaling pathway. Curr Opin Cell Biol. 2005;17(2):150-7. https://doi.org/10.1016/j.ceb.2005.02.010PMid:15780591 Yang W, Liu Y, Xu QQ, Xian YF, Lin ZX. Sulforaphene Ameliorates Neuroinflammation and Hyperphosphorylated Tau Protein via Regulating the PI3K/Akt/GSK-3β Pathway in Experimental Models of Alzheimer's Disease. Oxid Med Cell Longev. 2020;2020:4754195. https://doi.org/10.1155/2020/4754195PMid:32963694 PMCid:PMC7502131 Dai S, Zhou F, Sun J, Li Y. NPD1 Enhances Autophagy and Reduces Hyperphosphorylated Tau and Amyloid-β42 by Inhibiting GSK3β Activation in N2a/APP695swe Cells. J Alzheimers Dis. 2021;84(2):869-81. https://doi.org/10.3233/JAD-210729PMid:34602482 Imamura T, Yanagihara YT, Ohyagi Y, Nakamura N, Iinuma KM, Yamasaki R, et al. Insulin deficiency promotes formation of toxic amyloid-β42 conformer co-aggregating with hyper-phosphorylated tau oligomer in an Alzheimer's disease model. Neurobiol Dis. 2020;137:104739. https://doi.org/10.1016/j.nbd.2020.104739PMid:31927145 Chen Q, Lu H, Duan C, Zhu X, Zhang Y, Li M, et al. PDCD4 Simultaneously Promotes Microglia Activation via PDCD4-MAPK-NF-κB Positive Loop and Facilitates Neuron Apoptosis During Neuroinflammation. Inflammation. 2022;45(1):234-52. https://doi.org/10.1007/s10753-021-01541-9PMid:34613548 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. https://doi.org/10.1016/S1474-4422(20)30440-3PMid:33609479 Mantzavinos V, Alexiou A. Biomarkers for Alzheimer's Disease Diagnosis. Curr Alzheimer Res. 2017;14(11):1149-54. https://doi.org/10.2174/1567205014666170203125942PMid:28164766 PMCid:PMC5684784 Kabekkodu SP, Shukla V, Varghese VK, J DS, Chakrabarty S, Satyamoorthy K. Clustered miRNAs and their role in biological functions and diseases. Biol Rev Camb Philos Soc. 2018;93(4):1955-86. https://doi.org/10.1111/brv.12428PMid:29797774 Jiang D, Gong F, Ge X, Lv C, Huang C, Feng S, et al. Neuron-derived exosomes-transmitted miR-124-3p protect traumatically injured spinal cord by suppressing the activation of neurotoxic microglia and astrocytes. J Nanobiotechnology. 2020;18(1):105. https://doi.org/10.1186/s12951-020-00665-8PMid:32711535 PMCid:PMC7382861 Tao W, Yu L, Shu S, Liu Y, Zhuang Z, Xu S, et al. miR-204-3p/Nox4 Mediates Memory Deficits in a Mouse Model of Alzheimer's Disease. Mol Ther. 2021;29(1):396-408. https://doi.org/10.1016/j.ymthe.2020.09.006PMid:32950103 PMCid:PMC7791017 Xia P, Chen J, Liu Y, Cui X, Wang C, Zong S, et al. MicroRNA-22-3p ameliorates Alzheimer's disease by targeting SOX9 through the NF-κB signaling pathway in the hippocampus. J Neuroinflammation. 2022;19(1):180. https://doi.org/10.1186/s12974-022-02548-1PMid:35821145 PMCid:PMC9277852 Wang X, Liu D, Huang HZ, Wang ZH, Hou TY, Yang X, et al. A Novel MicroRNA-124/PTPN1 Signal Pathway Mediates Synaptic and Memory Deficits in Alzheimer's Disease. Biol Psychiatry. 2018;83(5):395-405. https://doi.org/10.1016/j.biopsych.2017.07.023PMid:28965984 Liu HY, Zhang YY, Zhu BL, Feng FZ, Yan H, Zhang HY, et al. miR-21 regulates the proliferation and apoptosis of ovarian cancer cells through PTEN/PI3K/AKT. Eur Rev Med Pharmacol Sci. 2019;23(10):4149-55. Chai C, Song LJ, Han SY, Li XQ, Li M. MicroRNA-21 promotes glioma cell proliferation and inhibits senescence and apoptosis by targeting SPRY1 via the PTEN/PI3K/AKT signaling pathway. CNS Neurosci Ther. 2018;24(5):369-80. https://doi.org/10.1111/cns.12785PMid:29316313 PMCid:PMC6489721 Xu G, Ao R, Zhi Z, Jia J, Yu B. miR-21 and miR-19b delivered by hMSC-derived EVs regulate the apoptosis and differentiation of neurons in patients with spinal cord injury. J Cell Physiol. 2019;234(7):10205-17. https://doi.org/10.1002/jcp.27690PMid:30387159 Fu X, He Y, Wang X, Peng D, Chen X, Li X, et al. Overexpression of miR-21 in stem cells improves ovarian structure and function in rats with chemotherapy-induced ovarian damage by targeting PDCD4 and PTEN to inhibit granulosa cell apoptosis. Stem Cell Res Ther. 2017;8(1):187. https://doi.org/10.1186/s13287-017-0641-zPMid:28807003 PMCid:PMC5556338 Xiao J, Pan Y, Li XH, Yang XY, Feng YL, Tan HH, et al. Cardiac progenitor cell-derived exosomes prevent cardiomyocytes apoptosis through exosomal miR-21 by targeting PDCD4. Cell Death Dis. 2016;7(6):e2277. https://doi.org/10.1038/cddis.2016.181PMid:27336721 PMCid:PMC5143405 Cheng Y, Liu X, Zhang S, Lin Y, Yang J, Zhang C. MicroRNA-21 protects against the H(2)O(2)-induced injury on cardiac myocytes via its target gene PDCD4. J Mol Cell Cardiol. 2009;47(1):5-14. https://doi.org/10.1016/j.yjmcc.2009.01.008PMid:19336275 PMCid:PMC3593965 Deng S, Dai G, Chen S, Nie Z, Zhou J, Fang H, et al. Dexamethasone induces osteoblast apoptosis through ROS-PI3K/AKT/GSK3β signaling pathway. Biomed Pharmacother. 2019;110:602-8. https://doi.org/10.1016/j.biopha.2018.11.103PMid:30537677 Lyu D, Jia J. Cryptotanshinone Attenuates Amyloid-β(42)-induced Tau Phosphorylation by Regulating PI3K/Akt/GSK3β Pathway in HT22 Cells. Mol Neurobiol. 2022;59(7):4488-500. https://doi.org/10.1007/s12035-022-02850-2PMid:35575872 Lauretti E, Dincer O, Praticò D. Glycogen synthase kinase-3 signaling in Alzheimer's disease. Biochim Biophys Acta Mol Cell Res. 2020;1867(5):118664. https://doi.org/10.1016/j.bbamcr.2020.118664PMid:32006534 PMCid:PMC7047718 Ni H, Han Y, Jin X. Celastrol inhibits colon cancer cell proliferation by downregulating miR-21 and PI3K/AKT/GSK-3β pathway. Int J Clin Exp Pathol. 2019;12(3):808-16. Zhao J, Zhang C, Gao Z, Wu H, Gu R, Jiang R. Long non-coding RNA ASBEL promotes osteosarcoma cell proliferation, migration, and invasion by regulating microRNA-21. J Cell Biochem. 2018;119(8):6461-9. https://doi.org/10.1002/jcb.26671PMid:29323740
Published
Issue
Section
License
Copyright (c) 2023 Galen Medical Journal
This work is licensed under a Creative Commons Attribution 4.0 International License.
