Skip to main content
SpringerLink
Log in

Effects of small interfering RNA targeting sphingosine kinase-1 gene on the animal model of Alzheimer’s disease

  • Published:
Journal of Huazhong University of Science and Technology [Medical Sciences] Aims and scope Submit manuscript

Summary

Alzheimer’s disease (AD) is an age-related, progressive neurodegenerative disorder that occurs gradually and results in memory, behavior, and personality changes. Abnormal sphingolipid metabolism was reported in AD previously. This study aimed to investigate whether sphK1 could exacerbate the accumulation of amyloid protein (Aβ) and sharpen the learning and memory ability of the animal model of AD using siRNA interference. An adenovirus vector expressing small interfering RNA (siRNA) against the sphK1 gene (sphK1-siRNA) was designed, and the effects of sphK1-siRNA on the APP/PS1 mouse four weeks after treatment with sphK1-siRNA hippocampal injection were examined. SphK1 protein expression was confirmed by using Western blotting and ceramide content coupled with S1P secretion was evaluated by enzyme-linked immunosorbent assay (ELISA). Aβ load was detected by immunohistochemical staining and ELISA. Morris water maze was adopted to test the learning and memory ability of the APP/PS1 mice. A significant difference in the expression of sphK1 protein and mRNA was observed between the siRNA group and the control group. Aβ load in transfected mice was accelerated in vivo, with significant aggravation of the learning and memory ability. The sphK1 gene modulation in the Aβ load and the learning and memory ability in the animal model of AD may be important for the treatment of AD.

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

Similar content being viewed by others

References

  1. Selkoe D. The deposition of amyloid proteins in the aging mammalian brain: implications for Alzheimer’s disease. Ann Med, 1989,21(2):73–76

    Article  PubMed  CAS  Google Scholar 

  2. He X, Huang Y, Li B, et al. Deregulation of sphingolipid metabolism in Alzheimer’s disease. Neurobiol Aging 2010,31(3):398–408

    Article  PubMed  CAS  Google Scholar 

  3. Walsh DM, Selkoe DJ. Aβ oligomers-a decade of discovery. J Neurochem, 2007,101(5):1172–1184

    Article  PubMed  CAS  Google Scholar 

  4. Kirkitadze MD, Bitan G, Teplow DB. Paradigm shifts in Alzheimer’s disease and other neurodegenerative disorders: the emerging role of oligomeric assemblies. J Neurosci Res, 2002,69(5):567–577

    Article  PubMed  CAS  Google Scholar 

  5. Shankar GM, Li S, Mehta TH, et al. Amyloid-β protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med, 2008,14(8): 837–842

    Article  PubMed  CAS  Google Scholar 

  6. Näslund J, Haroutunian V, Mohs R, et al. Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA, 2000,283(12): 1571–1577

    Article  PubMed  Google Scholar 

  7. Hannun YA, Obeid LM. The ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind. J Biol Chem, 2002,277(29):25847–25850

    Article  PubMed  CAS  Google Scholar 

  8. Spiegel S, Milstien S. Sphingosine-1-phosphate: an enigmatic signalling. Nat Rev Mol Cell Biol, 2003,4(5): 397–407

    Article  PubMed  CAS  Google Scholar 

  9. Bryan L, Kordula T, Spiegel S, et al. Regulation and functions of sphingosine kinases in the brain. Biochim Biophys Acta, 2008,1781(9):459–466

    Article  PubMed  CAS  Google Scholar 

  10. Gomez-Brouchet A, Pchejetski D, Brizuela L, et al. Critical role for sphingosine kinase-1 in regulating survival of neuroblastoma cells exposed to amyloid-beta peptide. Mol Pharmacol, 2007,72(2):341–349

    Article  PubMed  CAS  Google Scholar 

  11. Van Brocklyn JR, Jackson CA, Pearl DK, et al. Sphingosine kinase-1 expression correlates with poor survival of patients with glioblastoma multiforme: roles of sphingosine kinase isoforms in growth of glioblastoma cell lines. J Neuropathol Exp Neurol, 2005,64(8):695–705

    Article  PubMed  Google Scholar 

  12. Liu H, Sugiura M, Nava VE, et al. Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform. J Biol Chem, 2000,275(26): 19513–19520

    Article  PubMed  CAS  Google Scholar 

  13. Spiegel S, Milstien S. Functions of the multifaceted family of sphingosine kinases and some close relatives. J Biol Chem, 2007,282(4):2125–2129

    Article  PubMed  CAS  Google Scholar 

  14. Anelli V, Gault CR, Cheng AB, et al. Sphingosine kinase 1 is upregulated during hypoxia in U87MG glioma cells: role of hypoxia-inducible factors 1 and 2. J Biol Chem, 2008,283(6):3365–3375

    Article  PubMed  CAS  Google Scholar 

  15. Shinpo K, Kikuchi S, Moriwaka F, et al. Protective effects of the TNF-ceramide pathway against glutamate neurotoxicity on cultured mesencephalic neurons. Brain Res, 1999,819(1–2):170–173

    Article  PubMed  CAS  Google Scholar 

  16. Kajimoto T, Okada T, Yu H, et al. Involvement of sphingosine-1-phosphate in glutamate secretion in hippocampal neurons. Mol Cell Biol, 2007,27(9):3429–3440

    Article  PubMed  CAS  Google Scholar 

  17. Robbins PD, Ghivizzani SC. Viral vectors for gene therapy. Pharmacol Ther, 1998,80(1):35–47

    Article  PubMed  CAS  Google Scholar 

  18. Chang KA, Suh YH. Pathophysiological roles of amyloidogenic carboxy-terminal fragments of the β-amyloid precursor protein in Alzheimer’s disease. J Pharmacol Sci, 2005,97(4):461–471

    Article  PubMed  CAS  Google Scholar 

  19. Zhang YH, Fehrenbacher JC, Vasko MR, et al. Sphingosine-1-phosphate via activation of a G-protein-coupled receptor (s) enhances the excitability of rat sensory neurons. J Neurophysiol, 2006,96(3):1042–1052

    Article  PubMed  CAS  Google Scholar 

  20. Patil S, Melrose J, Chan C. Involvement of astroglial ceramide in palmitic acid-induced Alzheimer-like changes in primary neurons. Eur J Neurosci, 2007,26(8):2131–2141

    Article  PubMed  Google Scholar 

  21. Puglielli L, Ellis BC, Saunders, AJ, et al. Ceramide stabilizes beta-site amyloid precursor protein-cleaving enzyme 1 and promotes amyloid beta-peptide biogenesis. J Biol Chem, 2003,278(22):19777–19783

    Article  PubMed  CAS  Google Scholar 

  22. Tamboli IY, Prager K, Barth E, et al. Inhibition of glycosphingolipid biosynthesis reduces secretion of the beta-amyloid precursor protein and amyloid beta-peptide. J Biol Chem, 2005,280(30):28110–28117

    Article  PubMed  CAS  Google Scholar 

  23. Grimm MO, Grimm HS, Pätzold AJ, et al. Regulation of cholesterol and sphingomyelin metabolism by amyloid-β and presenilin. Nat Cell Biol, 2005,7(11):1118–1123

    Article  PubMed  CAS  Google Scholar 

  24. Palop JJ, Mucke L. Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci, 2010,13(7):812–818

    Article  PubMed  CAS  Google Scholar 

  25. Haughey NJ, Bandaru VV, Bae M, et al. Roles for dysfunctional sphingolipid metabolism in Alzheimer’s disease neuropathogenesis. Biochim Biophys Acta, 2010, 1801(8):878–886

    Article  PubMed  CAS  Google Scholar 

  26. Yu N, Lariosa-Willingham KD, Lin FF, et al. Characterization of lysophosphatidic acid and sphingosine-1-phosphate-mediated signal transduction in rat cortical oligodendrocytes. Glia, 2004,45(1):17–27

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Yuan Zhang  (张 远), Yang Yang  (杨 阳), Gang Li  (黎 刚) & Sheng-gang Sun  (孙圣刚)

  2. Department of Neurology, Shandong Qianfoshan Hospital, Jinan, 250014, China

    Yuan Zhang  (张 远)

  3. Department of Osteology, Shandong Qianfoshan Hospital, Jinan, 250014, China

    Qian Yu  (禹 虔)

  4. Department of Neurology, Zhongshan Hospital, Xiamen University, Xiamen, 361004, China

    Tian-bao Lai  (赖天宝)

Authors
  1. Yuan Zhang  (张 远)
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qian Yu  (禹 虔)
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tian-bao Lai  (赖天宝)
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yang Yang  (杨 阳)
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gang Li  (黎 刚)
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sheng-gang Sun  (孙圣刚)
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gang Li  (黎 刚).

Additional information

These authors contributed equally to this work.

This project was supported by the National Natural Science Foundation of China (No. 81070879).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, Y., Yu, Q., Lai, Tb. et al. Effects of small interfering RNA targeting sphingosine kinase-1 gene on the animal model of Alzheimer’s disease. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 33, 427–432 (2013). https://doi.org/10.1007/s11596-013-1136-5

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11596-013-1136-5

Key words

Search

Navigation