Skip to main content

Advertisement

SpringerLink
Log in

DHT Inhibits the Aβ25–35-Induced Apoptosis by Regulation of Seladin-1, Survivin, XIAP, bax, and bcl-xl Expression Through a Rapid PI3-K/Akt Signaling in C6 Glial Cell Lines

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

Abstract

Previous evidences indicate that androgen is neuroprotective in the brain. However, the underling mechanisms remain to be fully elucidated. Moreover, it is controversial whether dihydrotestosterone (DHT) modulates the expression of apoptosis-related effectors, such as survivin, XIAP, bax, and bcl-xl proteins mediated by the PI3-K/Akt pathway, which contributes to androgen neuroprotection. In this study using a C6 glial cell model, apoptotic cells were detected by flow cytometry. Akt, seladin-1, survivin, XIAP, bcl-xl, and bax protein expression is investigated by Western blot. After amyloid β-protein fragment (Aβ25–35) treatment, apoptotic cells at early (annexin V+, PI−) and late (annexin V+, PI+) stages were significantly increased. Apoptosis at early and late was obviously inhibited in the presence of DHT. The effect of DHT was markedly blocked by PI3-K inhibitor LY294002.To elicit the mechanism of DHT protection, the expression of seladin-1, survivin, XIAP, bax, and bcl-xl protein was determined in C6 cells treated with Aβ25–35, DHT, or LY294002. Aβ25–35 significantly downregulated the expression of seladin-1, survivin, XIAP, bcl-xl protein and upregulated the expression of bax protein. DHT significantly inhibited the expression of bax, seladin-1, survivin, XIAP, and bcl-xl protein induced by Aβ25–35. Further, we found the effect of DHT was significantly inhibited by LY294002. Collectively, in a C6 glial cell model, we firstly found that DHT inhibits Aβ25–35-induced apoptosis by a rapid nongenic PI-3K/Akt activation as well as regulation of seladin-1, survivin, XIAP, bcl-xl, and bax proteins.

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

Similar content being viewed by others

References

  1. Rosario ER, Chang L, Stanczyk FZ, Pike CJ (2004) Age-related testosterone depletion and the development of Alzheimer disease. JAMA 292(12):1431–1432

    Article  CAS  PubMed  Google Scholar 

  2. Carroll JC, Rosario ER (2012) The potential use of hormone-based therapeutics for the treatment of Alzheimer’s disease. Curr Alzheimer Res 9(1):18–34

    Article  CAS  PubMed  Google Scholar 

  3. Seyedreza P, Alireza MN, Seyedebrahim H (2012) Role of testosterone in memory impairment of Alzheimer disease induced by Streptozotocin in male rats. Daru 20(1):98

    Article  PubMed Central  PubMed  Google Scholar 

  4. Pike CJ, Carroll JC, Rosario ER, Barron AM (2009) Protective actions of sex steroid hormones in Alzheimer’s disease. Front Neuroendocrinol 30(2):239–258

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Pike CJ, Nguyen T-Vi V, Ramsden M, Yao M, Murphy MP, Rosario ER (2008) Androgen cell signaling pathways involved in neuroprotective actions. Horm Behav 53(5):693–705

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Kalaria RN (1999) Microglia and Alzheimer’s disease. Curr Opin Hematol 6(1):15–24

    Article  CAS  PubMed  Google Scholar 

  7. Bachoo RM, Kim RS, Ligon KL, Maher EA, Brennan C, Billings N, Chan S, Li C, Rowitch DH, Wong WH, DePinho RA (2004) Molecular diversity of astrocytes with implications for neurological disorders. Proc Natl Acad Sci USA 101(22):8384–8389

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Gatson JW, Singh M (2007) Activation of a membrane-associated androgen receptor promotes cell death in primary cortical astrocytes. Endocrinology 148(5):2458–2464

    Article  CAS  PubMed  Google Scholar 

  9. Foradori CD, Weiser MJ, Handa RJ (2008) Non-genomic actions of androgens. Front Neuroendocrinol 29(2):169–181

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Yamagishi S, Yamada M, Koshimizu H, Takai S, Hatanaka H, Takeda K, Ichijo H, Shimoke K, Ikeuchi T (2003) Apoptosis-signal regulating kinase-1 is involved in the low potassium-induced activation of p38 mitogen-activated protein kinase and c-Jun in cultured cerebellar granule neurons. J Biochem 133(6):719–724

    Article  CAS  PubMed  Google Scholar 

  11. Gatson JW, Kaur P, Singh M (2006) Dihydrotestosterone differentially modulates the mitogen-activated protein kinase and the phosphoinositide 3-kinase/Akt pathways through the nuclear and novel membrane androgen receptor in C6 cells. Endocrinology 147(4):2028–2034

    Article  CAS  PubMed  Google Scholar 

  12. Xia Y, Cheng Z, Wang JL, Noelle C, Anastasio K, Johnson M (2010) Brain-derived neurotrophic factor prevents phencyclidine-induced apoptosis in developing brain by parallel activation of both the ERK and PI-3K/Akt pathways. Neuropharmacology 58(2):330

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Nguyen N, Lee SB, Lee YS, Lee KH, Ahn JY (2009) Neuroprotection by NGF and BDNF against neurotoxin-exerted apoptotic death in neural stem cells are mediated through Trk receptors, activating PI3-kinase and MAPK pathways. Neurochem Res 34(5):942–951

    Article  CAS  PubMed  Google Scholar 

  14. Kudo W, Lee HP, Smith MA, Zhu X, Matsuyama S, Lee HG (2012) Inhibition of Bax protects neuronal cells from oligomeric Aβ neurotoxicity. Cell Death Dis 3(5):e309

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Semaan SJ, Murray EK, Poling MC, Dhamija S, Forger NG, Kauffman AS (2010) BAX-dependent and BAX-independent regulation of Kiss1 neuron development in mice. Endocrinology 151(12):5807–5817

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Shang YC, Chong ZZ, Wang S, Maiese K (2012) Prevention of β-amyloid degeneration of microglia by erythropoietin depends on Wnt1, the PI 3-K/mTOR pathway, Bad, and Bcl-xL. Aging (Albany NY) 4(3):187–201

    CAS  Google Scholar 

  17. Pfister B, Oyler G, Betenbaugh M, Bao G (2004) The effects of BclXL and Bax over-expression on stretch-injury induced neural cell death. Mech Chem Biosyst 1(4):233–243

    PubMed  Google Scholar 

  18. Van DMF, Huang DC (2006) How the Bcl-2 family of proteins interact to regulate apoptosis. Cell Res 16(2):203–213

    Article  Google Scholar 

  19. Scorrano L, Korsmeyer SJ (2003) Mechanisms of cytochrome c release by proapoptotic BCL-2 family members. Biochem Biophys Res Commun 304(3):437–444

    Article  CAS  PubMed  Google Scholar 

  20. Degli EM, Dive C (2003) Mitochondrial membrane permeabilisation by Bax/Bak. Biochem Biophys Res Commun 304(3):455–461

    Article  Google Scholar 

  21. Kang MH, Reynolds CP (2009) Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res 15(4):1126–1132

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Chong ZZ, Li F, Maiese K (2005) Stress in the brain: novel cellular mechanisms of injury linked to Alzheimer’s disease. Brain Res Rev 49(1):1–21

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Greeve I, Hermans-Borgmeyer I, Brellinger C, Kasper D, Gomez-Isla T, Behl C, Levkau B, Nitsch RM (2000) The human DIMINUTO/DWARF1 homolog seladin-1 confers resistance to Alzheimer’s disease-associated neurodegeneration and oxidative stress. J Neurosci 20:7345–7352

    CAS  PubMed  Google Scholar 

  24. Alessandro P, Mario S (2008) Neuroprotective effects of the Alzheimer’s disease-related gene seladin-1. J Mol Endocrinol 41:251–261

    Article  Google Scholar 

  25. Peri A, Serio M (2008) Estrogen receptor-mediated neuroprotection: the role of the Alzheimer’s disease-related gene seladin-1. Neuropsychiat Dis Treat 4(4):817–824

    Article  CAS  Google Scholar 

  26. Zu H, Wu J, Zhang J, Yu M, Hong Z (2012) Testosterone up-regulates seladin-1 expression by iAR and PI3-K/Akt signaling pathway in C6 cells. Neurosci Lett 514(1):122–126

    Article  CAS  PubMed  Google Scholar 

  27. Altieri DC (2010) Survivin and IAP proteins in cell-death mechanisms. Biochem J 430(2):199–205

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Maier JK, Lahoua Z, Gendron NH, Fetni R, Johnston A, Davoodi J, Rasper D, Roy S, Slack RS, Nicholson DW, MacKenzie AE (2002) The neuronal apoptosis inhibitory protein is a direct inhibitor of caspases 3 and 7. J Neurosci 22(6):2035–2043

    CAS  PubMed  Google Scholar 

  29. Robertson GS, Crocker SJ, Nicholson DW, Schulz JB (2000) Neuroprotection by the inhibition of apoptosis. Brain Pathol 10(2):283–292

    Article  CAS  PubMed  Google Scholar 

  30. Batrinos ML (2012) Testosterone and aggressive behavior in man. Int J Endocrinol Metab 10(3):563–568

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Filová B, Ostatníková D, Celec P, Hodosy J (2013) The effect of testosterone on the formation of brain structures. Cells Tissues Organs 197(3):169–177

    Article  PubMed  Google Scholar 

  32. Białek M, Zaremba P, Borowicz KK, Czuczwar SJ (2004) Neuroprotective role of testosterone in the nervous system. Pol J Pharmacol 56(5):509–518

    PubMed  Google Scholar 

  33. Gold SM, Voskuhl RR (2006) Testosterone replacement therapy for the treatment of neurological and neuropsychiatric disorders. Curr Opin Investig Drugs 7(7):625–630

    CAS  PubMed  Google Scholar 

  34. Spence RD, Voskuhl RR (2012) Neuroprotective effects of estrogens and androgens in CNS inflammation and neurodegeneration. Front Neuroendocrinol 33(1):105–115

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Gold SM, Voskuhl RR (2009) Estrogen and testosterone therapies in multiple sclerosis. Prog Brain Res 175:239–251

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Dienel GA (2012) Exploring and mapping the world of astrocytes. Neurochem Res 37(11):2295–2298

    Article  CAS  PubMed  Google Scholar 

  37. Rossi D, Volterra A (2009) Astrocytic dysfunction: insights on the role in neurodegeneration. Brain Res Bull 80(4–5):224–232

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by research Grants (No. 10411961900) from the Science and Technology Commission of Shanghai Municipality, Shanghai, China.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Neurology, Jinshan Hospital Affiliated to Fudan University, No. 1508 Longhang Road, Jinshan District, Shanghai, 201508, China

    Lelin Bing, Junfeng Wu, Jianfeng Zhang, Yinghui Chen & Hengbing Zu

  2. Department of Neurology, Huashan Hospital Affiliated to Fudan University, Shanghai, 200040, China

    Zhen Hong

Authors
  1. Lelin Bing
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Junfeng Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jianfeng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yinghui Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhen Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hengbing Zu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hengbing Zu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bing, L., Wu, J., Zhang, J. et al. DHT Inhibits the Aβ25–35-Induced Apoptosis by Regulation of Seladin-1, Survivin, XIAP, bax, and bcl-xl Expression Through a Rapid PI3-K/Akt Signaling in C6 Glial Cell Lines. Neurochem Res 40, 41–48 (2015). https://doi.org/10.1007/s11064-014-1463-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-014-1463-3

Keywords

Search

Navigation