Skip to main content

Advertisement

SpringerLink
Log in

SRY-Box 21 Antisense RNA 1 Knockdown Diminishes Amyloid Beta25–35-Induced Neuronal Damage by miR-132/PI3K/AKT Pathway

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Our study aimed to explore the function and mechanism of action of long noncoding RNA (lncRNA) SRY-Box 21 antisense RNA 1 (SOX21-AS1) in amyloid beta25–35 (Aβ25–35)-induced neuronal damage. To induce neuronal damage, neuronal cells and differentiated IMR-32 neuroblastoma cells were challenged by Aβ25–35. SOX21-AS1 and miR-132 quantities were detected by quantitative reverse transcription polymerase chain reaction. Cell damage was evaluated by detecting the changes of cell viability, apoptosis, and oxidative stress. Cell viability was measured using cell counting kit-8. Cell apoptosis was evaluated by flow cytometry and caspase-3 activity. The oxidative stress was analyzed by reactive oxygen species level. The expression of proteins associated with the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway was examined by western blot. SOX21-AS1 abundance was up-regulated in Aβ25–35-challenged neuronal cells. Silencing of SOX21-AS1 attenuated Aβ25–35-induced viability reduction and promotion of apoptosis and oxidative stress, suggesting that silencing of SOX21-AS1 repressed Aβ25–35-induced neuronal damage. miR-132 quantity was reduced in Aβ25–35-challenged neuronal cells, and negatively controlled by SOX21-AS1. miR-132 knockdown abolished the effect of SOX21-AS1 silencing on Aβ25–35-induced neuronal damage, indicating that SOX21-AS1 controls Aβ25–35-induced neuronal damage via regulating miR-132. The PI3K/AKT signaling was repressed in Aβ25–35-challenged cells, but this effect was counteracted upon overexpression of miR-132. In conclusion, SOX21-AS1 knockdown mitigated Aβ25–35-dependent neuronal cell damage by promoting miR-132/PI3K/AKT pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data Availability

The analyzed data sets generated during the study are available from the corresponding author on reasonable request.

References

  1. Long JM, Holtzman DM (2019) Alzheimer disease: an update on pathobiology and treatment strategies. Cell 179:312–339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wang J, Gu BJ, Masters CL, Wang YJ (2017) A systemic view of Alzheimer disease—insights from amyloid-β metabolism beyond the brain. Nat Rev Neurol 13:612–623

    Article  CAS  PubMed  Google Scholar 

  3. Forest KH, Nichols RA (2019) Assessing neuroprotective agents for Aβ-induced neurotoxicity. Trends Mol Med 25:685–695

    Article  CAS  PubMed  Google Scholar 

  4. Fricker M, Tolkovsky AM, Borutaite V, Coleman M, Brown GC (2018) Neuronal cell death. Physiol Rev 98:813–880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Butterfield DA, Halliwell B (2019) Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci 20:148–160

    Article  CAS  PubMed  Google Scholar 

  6. Oe S, Kimura T, Yamada H (2019) Regulatory non-coding RNAs in nervous system development and disease. Front Biosci (Landmark Ed) 24:1203–1240

    Article  CAS  Google Scholar 

  7. Maoz R, Garfinkel BP, Soreq H (2017) Alzheimer’s disease and ncRNAs. Adv Exp Med Biol 978:337–361

    Article  CAS  PubMed  Google Scholar 

  8. Maniati MS, Maniati M, Yousefi T, Ahmadi-Ahangar A, Tehrani SS (2019) New insights into the role of microRNAs and long noncoding RNAs in most common neurodegenerative diseases. J Cell Biochem 120:8908–8918

    Article  CAS  PubMed  Google Scholar 

  9. Cortini F, Roma F, Villa C (2019) Emerging roles of long non-coding RNAs in the pathogenesis of Alzheimer’s disease. Ageing Res Rev 50:19–26

    Article  CAS  PubMed  Google Scholar 

  10. Zhou M, Zhao H, Wang X, Sun J, Su J (2019) Analysis of long noncoding RNAs highlights region-specific altered expression patterns and diagnostic roles in Alzheimer’s disease. Brief Bioinform 20:598–608

    Article  CAS  PubMed  Google Scholar 

  11. Li X, Wang SW, Li XL, Yu FY, Cong HM (2020) Knockdown of long non-coding RNA TUG1 depresses apoptosis of hippocampal neurons in Alzheimer’s disease by elevating microRNA-15a and repressing ROCK1 expression. Inflamm Res 69:897–910

    Article  CAS  PubMed  Google Scholar 

  12. Gao Y, Zhang N, Lv C, Li N, Li X, Li W (2020) lncRNA SNHG1 knockdown alleviates amyloid-β-induced neuronal injury by regulating ZNF217 via sponging miR-361-3p in Alzheimer’s disease. J Alzheimers Dis 77:85–98

    Article  CAS  PubMed  Google Scholar 

  13. Xu W, Li K, Fan Q, Zong B, Han L (2020) Knockdown of long non-coding RNA SOX21-AS1 attenuates amyloid-β-induced neuronal damage by sponging miR-107. Biosci Rep 40:BSR20194295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Segaran RC, Chan LY, Wang H, Sethi G, Tang FR (2021) Neuronal development-related miRNAs as biomarkers for Alzheimer’s disease, depression, schizophrenia and ionizing radiation exposure. Curr Med Chem 28:19–52

    Article  CAS  PubMed  Google Scholar 

  15. El Fatimy R, Li S, Chen Z, Mushannen T, Gongala S, Wei Z, Balu DT, Rabinovsky R, Cantlon A, Elkhal A, Selkoe DJ, Sonntag KC, Walsh DM, Krichevsky AM (2018) MicroRNA-132 provides neuroprotection for tauopathies via multiple signaling pathways. Acta Neuropathol 136:537–555

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Salta E, De Strooper B (2017) microRNA-132: a key noncoding RNA operating in the cellular phase of Alzheimer’s disease. FASEB J 31:424–433

    Article  CAS  PubMed  Google Scholar 

  17. Wang X, Wang C, Geng C, Zhao K (2018) LncRNA XIST knockdown attenuates Aβ25-35-induced toxicity, oxidative stress, and apoptosis in primary cultured rat hippocampal neurons by targeting miR-132. Int J Clin Exp Pathol 11:3915–3924

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Rai SN, Dilnashin H, Birla H, Singh SS, Zahra W, Rathore AS, Singh BK, Singh SP (2019) The role of PI3K/Akt and ERK in neurodegenerative disorders. Neurotox Res 35:775–795

    Article  CAS  PubMed  Google Scholar 

  19. Wang Y, Chang Q (2020) MicroRNA miR-212 regulates PDCD4 to attenuate Aβ25-35-induced neurotoxicity via PI3K/AKT signaling pathway in Alzheimer’s disease. Biotechnol Lett 42:1789–1797

    Article  CAS  PubMed  Google Scholar 

  20. Wang T, Cheng Y, Han H, Liu J, Tian B, Liu X (2019) miR-194 accelerates apoptosis of aβ1-42-transduced hippocampal neurons by inhibiting Nrn1 and decreasing PI3K/Akt signaling pathway activity. Genes (Basel) 10:313

    Article  CAS  Google Scholar 

  21. Lian R, Lu B, Jiao L, Li S, Wang H, Miao W, Yu W (2016) MiR-132 plays an oncogenic role in laryngeal squamous cell carcinoma by targeting FOXO1 and activating the PI3K/AKT pathway. Eur J Pharmacol 792:1–6

    Article  CAS  PubMed  Google Scholar 

  22. Slanzi A, Iannoto G, Rossi B, Zenaro E, Constantin G (2020) In vitro models of neurodegenerative diseases. Front Cell Dev Biol 8:328

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ge Y, Song X, Liu J, Liu C, Xu C (2020) The combined therapy of berberine treatment with lncRNA BACE1-AS depletion attenuates Aβ25-35 induced neuronal injury through regulating the expression of miR-132-3p in neuronal cells. Neurochem Res 45:741–751

    Article  CAS  PubMed  Google Scholar 

  24. Sarkar B, Dhiman M, Mittal S, Mantha AK (2017) Curcumin revitalizes amyloid beta (25–35)-induced and organophosphate pesticides pestered neurotoxicity in SH-SY5Y and IMR-32 cells via activation of APE1 and Nrf2. Metab Brain Dis 32:2045–2061

    Article  CAS  PubMed  Google Scholar 

  25. Wang Y, Zheng ZJ, Jia YJ, Yang YL, Xue YM (2018) Role of p53/miR-155-5p/sirt1 loop in renal tubular injury of diabetic kidney disease. J Transl Med 16:146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods 25:402–408

    Article  CAS  PubMed  Google Scholar 

  27. Lopes TZ, de Moraes FR, Tedesco AC, Arni RK, Rahal P, Calmon MF (2020) Berberine associated photodynamic therapy promotes autophagy and apoptosis via ROS generation in renal carcinoma cells. Biomed Pharmacother 123:109794

    Article  CAS  PubMed  Google Scholar 

  28. Paraskevopoulou MD, Vlachos IS, Karagkouni D, Georgakilas G, Kanellos I, Vergoulis T, Zagganas K, Tsanakas P, Floros E, Dalamagas T, Hatzigeorgiou AG (2016) DIANA-LncBase v2: indexing microRNA targets on non-coding transcripts. Nucleic Acids Res 44:D231-238

    Article  CAS  PubMed  Google Scholar 

  29. Zhou P, Xu W, Peng X, Luo Z, Xing Q, Chen X, Hou C, Liang W, Zhou J, Wu X, Songyang Z, Jiang S (2013) Large-scale screens of miRNA-mRNA interactions unveiled that the 3’UTR of a gene is targeted by multiple miRNAs. PLoS ONE 8:68204

    Article  CAS  Google Scholar 

  30. Han L, Yue X, Zhou X, Lan FM, You G, Zhang W, Zhang KL, Zhang CZ, Cheng JQ, Yu SZ, Pu PY, Jiang T, Kang CS (2012) MicroRNA-21 expression is regulated by β-catenin/STAT3 pathway and promotes glioma cell invasion by direct targeting RECK. CNS Neurosci Ther 18:573–583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wang SH, Zhang WJ, Wu XC, Weng MZ, Zhang MD, Cai Q, Zhou D, Wang JD, Quan ZW (2016) The lncRNA MALAT1 functions as a competing endogenous RNA to regulate MCL-1 expression by sponging miR-363-3p in gallbladder cancer. J Cell Mol Med 20:2299–2308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jin Y, Chen Z, Liu X, Zhou X (2013) Evaluating the microRNA targeting sites by luciferase reporter gene assay. Methods Mol Biol 936:117–127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Torres M, Becquet D, Guillen S, Boyer B, Moreno M, Blanchard MP, Franc JL, François-Bellan AM (2018) RNA pull-down procedure to identify RNA targets of a long non-coding RNA. J Vis Exp 134:57379

    Google Scholar 

  34. Millan MJ (2017) Linking deregulation of non-coding RNA to the core pathophysiology of Alzheimer’s disease: an integrative review. Prog Neurobiol 156:1–68

    Article  CAS  PubMed  Google Scholar 

  35. Wang X, Shen C, Zhu J, Shen G, Li Z, Dong J (2019) Long noncoding RNAs in the regulation of oxidative stress. Oxid Med Cell Longev 2019:1318795

    PubMed  PubMed Central  Google Scholar 

  36. Wei AW, Li LF (2017) Long non-coding RNA SOX21-AS1 sponges miR-145 to promote the tumorigenesis of colorectal cancer by targeting MYO6. Biomed Pharmacother 96:953–959

    Article  CAS  PubMed  Google Scholar 

  37. Gai SY, Yuan ZH (2020) Long non-coding RNA SOX21-AS1 promotes cell proliferation and invasion through upregulating PAK7 expression by sponging miR-144-3p in glioma cells. Neoplasma 67:333–343

    Article  CAS  PubMed  Google Scholar 

  38. Liu X, Song J, Kang Y, Wang Y, Chen A (2020) Long noncoding RNA SOX21-AS1 regulates the progression of triple-negative breast cancer through regulation of miR-520a-5p/ORMDL3 axis. J Cell Biochem 121:4601–4611

    Article  CAS  PubMed  Google Scholar 

  39. Yang CM, Wang TH, Chen HC, Li SC, Lee MC, Liou HH, Liu PF, Tseng YK, Shiue YL, Ger LP, Tsai KW (2016) Aberrant DNA hypermethylation-silenced SOX21-AS1 gene expression and its clinical importance in oral cancer. Clin Epigenetics 8:129

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Zhang L, Fang Y, Cheng X, Lian YJ, Xu HL (2019) Silencing of long noncoding RNA SOX21-AS1 relieves neuronal oxidative stress injury in mice with alzheimer’s disease by upregulating FZD3/5 via the Wnt signaling pathway. Mol Neurobiol 56:3522–3537

    Article  CAS  PubMed  Google Scholar 

  41. Frozza RL, Horn AP, Hoppe JB, Simão F, Gerhardt D, Comiran RA, Salbego CG (2009) A comparative study of β-amyloid peptides Aβ1-42 and Aβ25-35 toxicity in organotypic hippocampal slice cultures. Neurochem Res 34:295–303

    Article  CAS  PubMed  Google Scholar 

  42. Wu YY, Kuo HC (2020) Functional roles and networks of non-coding RNAs in the pathogenesis of neurodegenerative diseases. J Biomed Sci 27:49

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Zhao Y, Zhao R, Wu J, Wang Q, Pang K, Shi Q, Gao Q, Hu Y, Dong X, Zhang J, Sun J (2018) Melatonin protects against Aβ-induced neurotoxicity in primary neurons via miR-132/PTEN/AKT/FOXO3a pathway. BioFactors 44:609–618

    Article  CAS  PubMed  Google Scholar 

  44. Xu N, Li AD, Ji LL, Ye Y, Wang ZY, Tong L (2019) miR-132 regulates the expression of synaptic proteins in APP/PS1 transgenic mice through C1q. Eur J Histochem 63:3008

    Article  PubMed Central  CAS  Google Scholar 

  45. Hernandez-Rapp J, Rainone S, Goupil C, Dorval V, Smith PY, Saint-Pierre M, Vallee M, Planel E, Droit A, Calon F, Cicchetti F, Hebert SS (2016) microRNA-132/212 deficiency enhances Aβ production and senile plaque deposition in Alzheimer’s disease triple transgenic mice. Sci Rep 6:30953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Barker RM, Holly JMP, Biernacka KM, Allen-Birt SJ, Perks CM (2020) Mini review: opposing pathologies in cancer and Alzheimer’s disease: does the PI3K/Akt pathway provide clues? Front Endocrinol (Lausanne) 11:403

    Article  Google Scholar 

  47. Matsuda S, Nakagawa Y, Tsuji A, Kitagishi Y, Nakanishi A, Murai T (2018) Implications of PI3K/AKT/PTEN signaling on superoxide dismutases expression and in the pathogenesis of Alzheimer’s disease. Diseases 6:28

    Article  PubMed Central  CAS  Google Scholar 

  48. Gu Y, Cai R, Zhang C, Xue Y, Pan Y, Wang J, Zhang Z (2019) miR-132-3p boosts caveolae-mediated transcellular transport in glioma endothelial cells by targeting PTEN/PI3K/PKB/Src/Cav-1 signaling pathway. FASEB J 33:441–454

    Article  CAS  PubMed  Google Scholar 

  49. Zhang CJ, Huang Y, Lu JD, Lin J, Ge ZR, Huang H (2019) Upregulated microRNA-132 rescues cardiac fibrosis and restores cardiocyte proliferation in dilated cardiomyopathy through the phosphatase and tensin homolog-mediated PI3K/Akt signal transduction pathway. J Cell Biochem 120:1232–1244

    Article  CAS  Google Scholar 

Download references

Funding

None.

Author information

Author notes

  1. Fengming Gu and Daofei Ji are Co-first authors.

Authors and Affiliations

  1. Department of Intensive Care Unit, The Affiliated Huai’an Hospital of Xuzhou Medical University, The Second People’s Hospital of Huai’an, Huai’an, 223002, China

    Fengming Gu

  2. Department of Neurosurgery, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, China

    Daofei Ji

  3. Department of Neurosurgery, The Affiliated Huai’an Hospital of Xuzhou Medical University, The Second People’s Hospital of Huai’an, Huai’an, 223002, China

    Hongzao Ni

  4. Department of Intensive Care Unit, People’s Hospital of Huai’an Hongze District, 102 Dongfeng Road, Huai’an, 223100, China

    Depeng Chen

Authors
  1. Fengming Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daofei Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hongzao Ni
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Depeng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Depeng Chen.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gu, F., Ji, D., Ni, H. et al. SRY-Box 21 Antisense RNA 1 Knockdown Diminishes Amyloid Beta25–35-Induced Neuronal Damage by miR-132/PI3K/AKT Pathway. Neurochem Res 46, 2376–2386 (2021). https://doi.org/10.1007/s11064-021-03373-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-021-03373-3

Keywords

Search

Navigation