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RETRACTED ARTICLE: Gene knockout of 5-lipoxygenase rescues synaptic dysfunction and improves memory in the triple-transgenic model of Alzheimer's disease

Molecular Psychiatry volume 19, pages 511–518 (2014)Cite this article

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This article was retracted on 05 October 2022

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Abstract

5-Lipoxygenase (5LO) is upregulated in Alzheimer’s disease (AD) and in vivo modulates the amyloidotic phenotype of amyloid precursor protein transgenic mice. However, no data are available on the effects that 5LO has on synaptic function, integrity and cognition. To address this issue, we used a genetic and a pharmacological approach by generating 3 × Tg mice deficient for 5LO and administering 3 × Tg mice with a 5LO inhibitor. Compared with controls, we found that even before the development of overt neuropathology, both animals manifested significant memory improvement, rescue of their synaptic dysfunction and amelioration of synaptic integrity. In addition, later in life, these mice had a significant reduction of Aβ and tau pathology. Our findings support a novel functional role for 5LO in regulating synaptic plasticity and memory. They establish this protein as a pleiotropic contributor to the development of the full spectrum of the AD phenotype, making it a valid therapeutic target for the treatment of AD.

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References

  1. Selkoe DJ . Alzheimer’s disease, genes, proteins, and therapy. Physiol Rev 2001; 81: 741–766.

    Article  CAS  Google Scholar 

  2. Sze CI, Troncoso JC, Kawas C, Mouton P, Price DL, Martin LJ . Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease. J Neuropathol Exp Neurol 1997; 56: 933–944.

    Article  CAS  Google Scholar 

  3. Sy M, Kitazawa M, Medeiros R, Whitman L, Cheng D, Lane TE et al. Inflammation induced by infection potentiates tau pathological features in transgenic mice. Am J Pathol 2011; 178: 2811–2822.

    Article  CAS  Google Scholar 

  4. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R et al. Physical basis of cognitive alterations in Alzheimer’s disease synapse loss is the major correlate of cognitive impairment. Ann Neurol 1991; 30: 572–580.

    Article  CAS  Google Scholar 

  5. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R et al. Triple transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 2003; 39: 409–421.

    Article  CAS  Google Scholar 

  6. Radmark O, Werz O, Steinhilber D, Samuelsson B . 5-Lipoxygenase: regulation of expression and enzyme activity. Trends Biochem Sci 2007; 32: 332–341.

    Article  CAS  Google Scholar 

  7. Chinnici CM, Yao Y, Praticò D . The 5-lipoxygenase enzymatic pathway in the mouse brain: young versus old. Neurobiol Aging 2007; 28: 1457–1462.

    Article  CAS  Google Scholar 

  8. Ikonomovic MD, Abrahamson EE, Uz T, Manev H, Dekosky ST . Increased 5-lipooxygenase immunoreactivity in hippocampus of patients with Alzheimer' diseases. J Histochem Cytochem 2008; 56: 1065–1073.

    Article  CAS  Google Scholar 

  9. Firuzi O, Zhuo J, Chinnici CM, Wisniewski T, Praticò D . 5-Lipoxygenase gene disruption reduces amyloid-β pathology in a mouse model of Alzheimer’s disease. FASEB J 2008; 22: 1169–1178.

    Article  CAS  Google Scholar 

  10. Chu J, Praticò D . Pharmacological blockade of 5-lipoxygenase improves the amyloidotic phenotype of an Alzheimer’s disease transgenic mouse model. Am J Pathol 2011; 178: 1762–1769.

    Article  CAS  Google Scholar 

  11. Chu J, Giannopoulos PF, Ceballos-Diaz C, Golde TE, Praticò D . 5-Lipoxygenase gene transfer worsens memory, amyloid, and tau brain pathologies in a mouse model of Alzheimer disease. Ann Neurol 2012; 72: 1762–1769.

    Article  Google Scholar 

  12. Goulet JL, Snouwaert JN, Latourt AM, Coffman TM, Koller BH . Altered inflammatory responses in leukotriene-deficient mice. Proc Natl Acad Sci 1994; 91: 12852–12856.

    Article  CAS  Google Scholar 

  13. Yang H, Zhuo J, Chu J, Chinnici C, Pratico D . Amelioration of the Alzheimer’s disease phenotype by absence of 12/15-lipoxygenase. Biol Psychiatry 2010; 68: 922–929.

    Article  CAS  Google Scholar 

  14. Zhuo JM, Portugal GS, Kruger WD, Wang H, Gould T, Pratico D . Diet-induced hyperhomocysteinemia increases amyloid-beta formation and deposition in a mouse model of Alzheimer’s disease. Curr Alzheimer Res 2010; 7: 140–149.

    Article  CAS  Google Scholar 

  15. Andorfer C, Kress Y, Espinoza M, de Silva R, Tucker KL, Barde YA et al. Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem 2003; 86: 582–590.

    Article  CAS  Google Scholar 

  16. Zucker RS, Regehr WG . Short-term synaptic plasticity. Annu Rev Physiol 2002; 64: 355–405.

    Article  CAS  Google Scholar 

  17. Bliss TVP, Collingridge GL . A synaptic model of memory: long-term potentiation in the hippocampus. Nature 1993; 361: 31–39.

    Article  CAS  Google Scholar 

  18. DeKosky ST, Scheff SW . Synapse loss in frontal cortex biopsies in Alzheimer’s disease correlation with cognitive severity. Ann Neurol 1990; 27: 457–464.

    Article  CAS  Google Scholar 

  19. Scheff SW, Scott SA, DeKosky ST . Quantitation of synaptic density in the septal nuclei of young and aged Fischer 344 rats. Neurobiol Aging 1991; 12: 3–12.

    Article  CAS  Google Scholar 

  20. Dickson DW, Crystal HA, Bevona C, Honer W, Vincent I, Davies P . Correlations of synaptic and pathological markers with cognition of the elderly. Neurobiol Aging 1995; 16: 285–304.

    Article  CAS  Google Scholar 

  21. Masliah E, Mallory M, Alford M, DeTeresa R, Hansen LA, McKeel DW et al. Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurology 2001; 56: 127–129.

    Article  CAS  Google Scholar 

  22. Hessler NA, Shirke AM, Malinow R . The probability of transmitter release at a mammalian central synapse. Nature 1993; 366: 569–572.

    Article  CAS  Google Scholar 

  23. Imbesi M, Zavoreo I, Uz T, Sharma RP, Dimitrijevic N, Manev H et al. 5-Lipoxygenase inhibitor MK-886 increases GluR1 phosphorylation in neuronal cultures in vitro and in the mouse cortex in vivo. Brain Res 2007; 1147: 148–153.

    Article  CAS  Google Scholar 

  24. Chen H, Manev H . Effects of minocycline on cocaine sensitization and phosphorylation of GluR1 receptors in 5-lipoxygenase deficient mice. Neuropharmacology 2011; 60: 1058–1063.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by the US National Institute of Health (NIH) Grants AG033568, NS071096 to DP; P30 DA 13429 and T32 DA 07237 to the Center for Substance Abuse Research. Additional support was provided by a grant from the Alzheimer Art Quilt Initiative to DP.

Author Contributions

PFG and DP designed the study, developed the experimental design, performed data analyses and wrote the paper. PFG, JC, YBJ, JL and MS performed the experiments. PFG, MS and LGK designed and performed electrophysiology experiments. All the authors discussed the results and commented on the manuscript.

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Authors and Affiliations

  1. Center for Translational Medicine and Temple University School of Medicine, Philadelphia, PA, USA

    P F Giannopoulos, J Chu, Y B Joshi, J-G Li & D Praticò

  2. Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA

    P F Giannopoulos, J Chu, Y B Joshi, J-G Li & D Praticò

  3. Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA

    M Sperow & L G Kirby

  4. Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA, USA

    L G Kirby

Authors
  1. P F Giannopoulos
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  2. J Chu
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  3. Y B Joshi
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  4. M Sperow
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  5. J-G Li
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  6. L G Kirby
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  7. D Praticò
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Corresponding author

Correspondence to D Praticò.

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The authors declare no conflict of interest.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website

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Giannopoulos, P., Chu, J., Joshi, Y. et al. RETRACTED ARTICLE: Gene knockout of 5-lipoxygenase rescues synaptic dysfunction and improves memory in the triple-transgenic model of Alzheimer's disease. Mol Psychiatry 19, 511–518 (2014). https://doi.org/10.1038/mp.2013.23

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  • DOI: https://doi.org/10.1038/mp.2013.23

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