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Knockdown of miR-429 Attenuates Aβ-Induced Neuronal Damage by Targeting SOX2 and BCL2 in Mouse Cortical Neurons

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Abstract

Accumulation of amyloid-β peptide (Aβ) and massive neuronal death due to apoptosis were the essential steps in the pathogenesis of Alzheimer’s disease (AD). MiR-429 was reported to play an important role in the pathogenesis of AD. However, the detailed function and underlying molecular mechanism of miR-429 in the pathogenesis of AD remain elusive. Cortical neurons were stimulated with 20 µM of Aβ25−35 for 24 h to construct AD model in vitro. qRT-PCR assay was used to detect the expression of miR-429, and qRT-PCR or western blot analysis were performed to assess the levels of Sex-determining region Y-box 2 (SOX2) and B cell lymphoma-2 protein (BCL2) at mRNA or proteins levels in the AD mouse model and Aβ-induced treated cortical neurons. Luciferase reporter assay and western blot analysis were used to confirm the potential targets of miR-429. CCK-8 assay, flow cytometry analysis, and caspase3 activity assay were used to measure cell viability, cell apoptosis capacity and caspase3 activity, respectively. MiR-429 was upregulated and SOX2 and BCL2 were downregulated in the AD mouse model and Aβ-induced mouse cortical neurons. MiR-429 knockdown attenuated Aβ-induced cytotoxicity in mouse cortical neurons. SOX2 and BCL2 were direct targets of miR-429. Moreover, anti-miR-429-mediated neuroprotective effect was abated by the restoration of SOX2 or BCL2 expression. Knockdown of miR-429 might attenuate Aβ-induced cytotoxicity by targeting SOX2 and BCL2 in mouse cortical neurons, providing a novel prospect in AD therapy.

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Abbreviations

Aβ:

Accumulation of amyloid-β peptide

AD:

Alzheimer’s disease

SOX2:

Sex-determining region Y-box 2

BCL2:

B cell lymphoma-2 protein

NFTs:

Neurofibrillary tangles

APP:

Amyloid precursor protein

BACE1:

β-site APP cleaving enzyme-1

SDS-PAGE:

Odium dodecyl sulfate polyacrylamide gel

References

  1. Alzheimer’s Association (2016) 2016 Alzheimer’s disease facts and figures. Alzheimer’s Dement 12:459–509

    Article  Google Scholar 

  2. Ossenkoppele R, Pijnenburg YA, Perry DC, Cohn-Sheehy BI, Scheltens NM, Vogel JW, Kramer JH, van der Vlies AE, La Joie R, Rosen HJ, van der Flier WM, Grinberg LT, Rozemuller AJ, Huang EJ, van Berckel BN, Miller BL, Barkhof F, Jagust WJ, Scheltens P, Seeley WW, Rabinovici GD (2015) The behavioural/dysexecutive variant of Alzheimer’s disease: clinical, neuroimaging and pathological features. Brain 138:2732–2749. https://doi.org/10.1093/brain/awv191

    Article  PubMed  PubMed Central  Google Scholar 

  3. Sun X, Chen WD, Wang YD (2015) beta-Amyloid: the key peptide in the pathogenesis of Alzheimer’s disease. Front Pharmacol 6:221. https://doi.org/10.3389/fphar.2015.00221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Eckert A, Keil U, Marques CA, Bonert A, Frey C, Schussel K, Muller WE (2003) Mitochondrial dysfunction, apoptotic cell death, and Alzheimer’s disease. Biochem Pharmacol 66:1627–1634

    Article  CAS  Google Scholar 

  5. Hammond SM (2015) An overview of microRNAs. Adv Drug Deliv Rev 87:3–14. https://doi.org/10.1016/j.addr.2015.05.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Tüfekci KU, Meuwissen RL, Genç S (2014) The role of microRNAs in biological processes. Methods Mol Biol 1107:33–50. https://doi.org/10.1007/978-1-62703-748-8_3

    Article  CAS  PubMed  Google Scholar 

  7. Femminella GD, Ferrara N, Rengo G (2015) The emerging role of microRNAs in Alzheimer’s disease. Front Physiol 6:40. https://doi.org/10.3389/fphys.2015.00040

    Article  PubMed  PubMed Central  Google Scholar 

  8. Absalon S, Kochanek DM, Raghavan V, Krichevsky AM (2013) MiR-26b, upregulated in Alzheimer’s disease, activates cell cycle entry, tau-phosphorylation, and apoptosis in postmitotic neurons. J Neurosci 33:14645–14659. https://doi.org/10.1523/jneurosci.1327-13.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Li YY, Cui JG, Hill JM, Bhattacharjee S, Zhao Y, Lukiw WJ (2011) Increased expression of miRNA-146a in Alzheimer’s disease transgenic mouse models. Neurosci Lett 487:94–98. https://doi.org/10.1016/j.neulet.2010.09.079

    Article  CAS  PubMed  Google Scholar 

  10. Banzhaf-Strathmann J, Benito E, May S, Arzberger T, Tahirovic S, Kretzschmar H, Fischer A, Edbauer D (2014) MicroRNA-125b induces tau hyperphosphorylation and cognitive deficits in Alzheimer’s disease. EMBO J 33:1667–1680. https://doi.org/10.15252/embj.201387576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wang X, Liu P, Zhu H, Xu Y, Ma C, Dai X, Huang L, Liu Y, Zhang L, Qin C (2009) miR-34a, a microRNA up-regulated in a double transgenic mouse model of Alzheimer’s disease, inhibits bcl2 translation. Brain Res Bull 80:268–273. https://doi.org/10.1016/j.brainresbull.2009.08.006

    Article  CAS  PubMed  Google Scholar 

  12. Luo H, Wu Q, Ye X, Xiong Y, Zhu J, Xu J, Diao Y, Zhang D, Wang M, Qiu J, Miao J, Zhang W, Wan J (2014) Genome-wide analysis of miRNA signature in the APPswe/PS1DeltaE9 mouse model of alzheimer’s disease. PLoS ONE 9:e101725. https://doi.org/10.1371/journal.pone.0101725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Barak B, Shvarts-Serebro I, Modai S, Gilam A, Okun E, Michaelson DM, Mattson MP, Shomron N, Ashery U (2013) Opposing actions of environmental enrichment and Alzheimer’s disease on the expression of hippocampal microRNAs in mouse models. Transl Psychiatry 3:e304. https://doi.org/10.1038/tp.2013.77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hu Y, Wen Q, Liang W, Kang T, Ren L, Zhang N, Zhao D, Sun D, Yang J (2013) Osthole reverses beta-amyloid peptide cytotoxicity on neural cells by enhancing cyclic AMP response element-binding protein phosphorylation. Biol Pharm Bull 36:1950–1958

    Article  CAS  Google Scholar 

  15. Karch CM, Goate AM (2015) Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry 77:43–51. https://doi.org/10.1016/j.biopsych.2014.05.006

    Article  CAS  PubMed  Google Scholar 

  16. Cancino GI, Toledo EM, Leal NR, Hernandez DE, Yevenes LF, Inestrosa NC, Alvarez AR (2008) STI571 prevents apoptosis, tau phosphorylation and behavioural impairments induced by Alzheimer’s beta-amyloid deposits. Brain 131:2425–2442. https://doi.org/10.1093/brain/awn125

    Article  PubMed  Google Scholar 

  17. Guo XD, Sun GL, Zhou TT, Xu X, Zhu ZY, Rukachaisirikul V, Hu LH, Shen X (2016) Small molecule LX2343 ameliorates cognitive deficits in AD model mice by targeting both amyloid beta production and clearance. Acta Pharmacol Sin 37:1281–1297. https://doi.org/10.1038/aps.2016.80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Resende R, Pereira C, Agostinho P, Vieira AP, Malva JO, Oliveira CR (2007) Susceptibility of hippocampal neurons to Abeta peptide toxicity is associated with perturbation of Ca2+ homeostasis. Brain Res 1143:11–21. https://doi.org/10.1016/j.brainres.2007.01.071

    Article  CAS  PubMed  Google Scholar 

  19. Tan L, Yu JT, Hu N, Tan L (2013) Non-coding RNAs in Alzheimer’s Disease. Mol Neurobiol 47:382–393

    Article  CAS  Google Scholar 

  20. Wu BW, Wu MS, Guo JD (2018) Effects of microRNA-10a on synapse remodeling in hippocampal neurons and neuronal cell proliferation and apoptosis through the BDNF-TrkB signaling pathway in a rat model of Alzheimer’s disease. J Cell Physiol 233:5281–5292. https://doi.org/10.1002/jcp.26328

    Article  CAS  PubMed  Google Scholar 

  21. Wong HK, Veremeyko T, Patel N, Lemere CA, Walsh DM, Esau C, Vanderburg C, Krichevsky AM (2013) De-repression of FOXO3a death axis by microRNA-132 and -212 causes neuronal apoptosis in Alzheimer’s disease. Hum Mol Genet 22:3077–3092. https://doi.org/10.1093/hmg/ddt164

    Article  CAS  PubMed  Google Scholar 

  22. He D, Tan J, Zhang J (2017) miR-137 attenuates Abeta-induced neurotoxicity through inactivation of NF-kappaB pathway by targeting TNFAIP1 in Neuro2a cells. Biochem Biophys Res Commun 490:941–947. https://doi.org/10.1016/j.bbrc.2017.06.144

    Article  CAS  PubMed  Google Scholar 

  23. Cogswell JP, Ward J, Taylor IA, Waters M, Shi Y, Cannon B, Kelnar K, Kemppainen J, Brown D, Chen C, Prinjha RK, Richardson JC, Saunders AM, Roses AD, Richards CA (2008) Identification of miRNA changes in Alzheimer’s disease brain and CSF yields putative biomarkers and insights into disease pathways. J Alzheimers Dis 14:27–41

    Article  CAS  Google Scholar 

  24. Zhang QS, Liu W, Lu GX (2017) miR-200a-3p promotes b-Amyloid-induced neuronal apoptosis through down-regulation of SIRT1 in Alzheimer’s disease. J Biosci 42:397–404. https://doi.org/10.1007/s12038-017-9698-1

    Article  CAS  PubMed  Google Scholar 

  25. Cannell IG, Kong YW, Bushell M (2008) How do microRNAs regulate gene expression? Sci Stke 2007:re1

    Google Scholar 

  26. Xue H, Tian GY (2018) MiR-429 regulates the metastasis and EMT of HCC cells through targeting RAB23. Arch Biochem Biophys 637:48–55. https://doi.org/10.1016/j.abb.2017.11.011

    Article  CAS  PubMed  Google Scholar 

  27. Sheng N, Zhang L, Yang S (2018) MicroRNA-429 decreases the invasion ability of gastric cancer cell line BGC-823 by downregulating the expression of heparanase. Exp Ther Med 15:1927–1933. https://doi.org/10.3892/etm.2017.5608

    Article  CAS  PubMed  Google Scholar 

  28. Zhang C, Chang C, Gao H, Wang Q, Zhang F, Xu C (2018) MiR-429 regulates rat liver regeneration and hepatocyte proliferation by targeting JUN/MYC/BCL2/CCND1 signaling pathway. Cell Signal 50:80–89. https://doi.org/10.1016/j.cellsig.2018.06.013

    Article  CAS  PubMed  Google Scholar 

  29. Li J, Du L, Yang Y, Wang C, Liu H, Wang L, Zhang X, Li W, Zheng G, Dong Z (2013) MiR-429 is an independent prognostic factor in colorectal cancer and exerts its anti-apoptotic function by targeting SOX2. Cancer Lett 329:84–90. https://doi.org/10.1016/j.canlet.2012.10.019

    Article  CAS  PubMed  Google Scholar 

  30. Sarlak G, Vincent B (2016) The roles of the stem cell-controlling Sox2 transcription factor: from neuroectoderm development to Alzheimer’s Disease? Mol Neurobiol 53:1679–1698. https://doi.org/10.1007/s12035-015-9123-4

    Article  CAS  PubMed  Google Scholar 

  31. Ferri AL, Cavallaro M, Braida D, Di CA, Canta A, Vezzani A, Ottolenghi S, Pandolfi PP, Sala M, Debiasi S (2004) Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain. Development 131:3805–3819

    Article  CAS  Google Scholar 

  32. Crews L, Adame A, Patrick C, Delaney A, Pham E, Rockenstein E, Hansen L, Masliah E (2010) Increased BMP6 levels in the brains of Alzheimer’s disease patients and APP transgenic mice are accompanied by impaired neurogenesis. J Neurosci 30:12252–12262. https://doi.org/10.1523/jneurosci.1305-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sarlak G, Htoo HH, Hernandez JF, Iizasa H, Checler F, Konietzko U, Song W, Vincent B (2016) Sox2 functionally interacts with betaAPP, the betaAPP intracellular domain and ADAM10 at a transcriptional level in human cells. Neuroscience 312:153–164. https://doi.org/10.1016/j.neuroscience.2015.11.022

    Article  CAS  PubMed  Google Scholar 

  34. Ola MS, Nawaz M, Ahsan H (2011) Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Mol Cell Biochem 351:41–58. https://doi.org/10.1007/s11010-010-0709-x

    Article  CAS  PubMed  Google Scholar 

  35. Ferreiro E, Eufrasio A, Pereira C, Oliveira CR, Rego AC (2007) Bcl-2 overexpression protects against amyloid-beta and prion toxicity in GT1-7 neural cells. J Alzheimers Dis 12:223–228

    Article  CAS  Google Scholar 

  36. Rohn TT, Vyas V, Hernandez-Estrada T, Nichol KE, Christie LA, Head E (2008) Lack of pathology in a triple transgenic mouse model of Alzheimer’s disease after overexpression of the anti-apoptotic protein Bcl-2. J Neurosci 28:3051–3059. https://doi.org/10.1523/jneurosci.5620-07.2008

    Article  CAS  PubMed  Google Scholar 

  37. Paradis E, Douillard H, Koutroumanis M, Goodyer C, LeBlanc A (1996) Amyloid beta peptide of Alzheimer’s disease downregulates Bcl-2 and upregulates bax expression in human neurons. J Neurosci 16:7533–7539

    Article  CAS  Google Scholar 

  38. Fang M, Wang J, Zhang X, Geng Y, Hu Z, Rudd JA, Ling S, Chen W, Han S (2012) The miR-124 regulates the expression of BACE1/β-secretase correlated with cell death in Alzheimer’s disease. Toxicol Lett 209:94–105. https://doi.org/10.1016/j.toxlet.2011.11.032

    Article  CAS  PubMed  Google Scholar 

  39. Higaki S, Muramatsu M, Matsuda A, Matsumoto K, Satoh JI, Michikawa M, Niida S (2018) Defensive effect of microRNA-200b/c against amyloid-beta peptide-induced toxicity in Alzheimer’s disease models. PLoS ONE 13:e0196929. https://doi.org/10.1371/journal.pone.0196929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mathew DE, Larsen K, Janeczek P, Lewohl JM (2016) Expression of 14-3-3 transcript isoforms in response to ethanol exposure and their regulation by miRNAs. Mol Cell Neurosci 75:44–49. https://doi.org/10.1016/j.mcn.2016.06.006

    Article  CAS  PubMed  Google Scholar 

  41. Zhou F, Zhang C, Guan Y, Chen Y, Lu Q, Jie L, Gao H, Du H, Zhang H, Liu Y, Wang X (2018) Screening the expression characteristics of several miRNAs in G93A-SOD1 transgenic mouse: altered expression of miRNA-124 is associated with astrocyte differentiation by targeting Sox2 and Sox9. J Neurochem 145:51–67. https://doi.org/10.1111/jnc.14229

    Article  CAS  PubMed  Google Scholar 

  42. Tryndyak VP, Ross SA, Beland FA, Pogribny IP (2009) Down-regulation of the microRNAs miR-34a, miR-127, and miR-200b in rat liver during hepatocarcinogenesis induced by a methyl-deficient diet. Mol Carcinog 48:479–487. https://doi.org/10.1002/mc.20484

    Article  CAS  PubMed  Google Scholar 

  43. Wang B, Li M, Wu Z, Li X, Li YU, Shi X, Cheng W (2015) Associations between SOX2 and miR-200b expression with the clinicopathological characteristics and prognosis of patients with glioma. Exp Ther Med 10:88–96. https://doi.org/10.3892/etm.2015.2488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Liu T, Wu C, Weng G, Zhao Z, He X, Fu C, Sui Z, Huang SX (2017) Bufalin inhibits cellular proliferation and cancer stem cell-like phenotypes via upregulation of MiR-203 in Glioma. Cell Physiol Biochem 44:671–681. https://doi.org/10.1159/000485279

    Article  PubMed  Google Scholar 

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Funding

This work was supported by the Project of Medical Science and Technology of Henan Province (Grant No. 201602197) and the National Nature Science Foundation of China (Grant No. 81671068).

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Authors and Affiliations

  1. Department of Neurology, People’s Hospital of Zhengzhou University, Zhengzhou, 45003, China

    Shengqi Fu & Jiewen Zhang

  2. Department of Neurology, People’s Hospital of Zhengzhou, Zhengzhou, 45003, China

    Shengqi Fu & Shuling Zhang

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  1. Shengqi Fu
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  2. Jiewen Zhang
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Correspondence to Jiewen Zhang.

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Fu, S., Zhang, J. & Zhang, S. Knockdown of miR-429 Attenuates Aβ-Induced Neuronal Damage by Targeting SOX2 and BCL2 in Mouse Cortical Neurons. Neurochem Res 43, 2240–2251 (2018). https://doi.org/10.1007/s11064-018-2643-3

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  • DOI: https://doi.org/10.1007/s11064-018-2643-3

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