Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Downregulation of autophagy by 12/15Lipoxygenase worsens the phenotype of an Alzheimer’s disease mouse model with plaques, tangles, and memory impairments

Molecular Psychiatry volume 26, pages 604–613 (2021)Cite this article

Subjects

Abstract

Among the different initiating events in Alzheimer’s disease (AD) pathogenesis, oxidative stress and neuroinflammation are some of the most iimportant. In the central nervous system, the 12/15Lipoxygenase (12/15LO) enzyme is the source of potent pro-oxidants and inflammatory lipid mediators. Previous works showed that this pathway is up-regulated in AD brains and that its pharmacological targeting modulates the phenotype of transgenic mouse models of the disease. Here we investigate the effect of brain 12/15LO gene delivery on the AD-like phenotype of a mouse model with plaques, tangles and behavioral deficits, the 3xTg mice. Compared with controls, mice over-expressing 12/15LO manifested an exacerbation of spatial learning and memory impairments, which was associated with significant increase in Aβ formation and deposition, and accumulation of hyper-phosphorylated insoluble tau secondary to a down-regulation of autophagy. In addition, the same mice manifested a worsening of neuroinflammation and synaptic pathology. Taken together our study supports the hypothesis that the 12/15LO enzymatic pathway by impairing neuronal autophagy plays a functional role in exacerbating AD-related neuropathologies and cognitive impairments. It provides further critical preclinical evidence to justify developing and testing new and selective 12/15LO inhibitors for AD treatment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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

Similar content being viewed by others

References

  1. Alzheimer’s Association. Alzheimer’s disease facts and figures. Alzheimer Dement. 2017;2017:325–73.

    Google Scholar 

  2. Martins RN, Villemagne V, Sohrabi HR, Chatterjee P, Shah TM, Verdile G, et al. Alzheimer’s disease: a journey from amyloid peptides and oxidative stress, to biomarker technologies and disease prevention strategies-gains from AIBL and DIAN cohort studies. J Alzheimer Dis. 2018;62:965–92.

    Article  CAS  Google Scholar 

  3. Mecocci P, Boccardi V, Cecchetti R, Bastiani P, Scamosci M, Ruggiero C, et al. A long journey into aging, brain aging, and Alzheimer’s disease following the oxidative stress tracks. J Alzheimer Dis. 2018;62:1319–35.

    Article  Google Scholar 

  4. Swanson A, Wolf T, Sitzmann A, Willette AA. Neuroinflammation in Alzheimer’s disease: pleiotropic roles for cytokines and neuronal pentraxins. Behav Brain Res. 2018;347:49–56.

    Article  CAS  Google Scholar 

  5. Mashima R, Okuyama T. LOX The role of lipoxygenases in pathophysiology; new insights and future perspectives. Redox Biol. 2015;6:297–310.

    Article  CAS  Google Scholar 

  6. Joshi YB, Giannopoulos PF, Praticò D. The 12/15-lipoxygenase as an emerging therapeutic target for Alzheimer’s disease. Trends Pharmacol Sci. 2015;36:181–6.

    Article  CAS  Google Scholar 

  7. Praticò D, Zhukareva V, Yao Y, Uryu U, Funk C, Lawson J, et al. 12/15Lipoxygenase is increased in Alzheimer’s disease: possible involvement in brain oxidative stress. Am J Pathol. 2004;164:1655–62.

    Article  Google Scholar 

  8. Yao Y, Clark CM, Trojanowski J, Lee V, Praticò D. Elevation of 12/15 lipoxygenase products in AD and mild cognitive impairment. Ann Neurol. 2005;58:623–6.

    Article  CAS  Google Scholar 

  9. Yang H, Zhuo J, Chu J, Chinnici C, Praticò D. Amelioration of the Alzheimer’s disease phenotype by absence of 12/15-lipoxygenase. Biol Psychiatry. 2010;68:922–9.

    Article  CAS  Google Scholar 

  10. Chu J, Giannopoulos PF, Blass B, Childers W, Abou-Garbia M, Praticò D. Pharmacologic blockade of 12/15-Lipoxygenase ameliorates memory deficits, Aβ and tau neuropathology in the triple transgenic mice. Mol Psychiatry. 2015;77:720–8.

    CAS  Google Scholar 

  11. Di Meco A, Li J-G, Blass B, Abou-Garbia M, Lauretti E, Praticò D. 12/15- Lipoxygenase inhibition reverses cognitive impairment, brain amyloidosis, and tau pathology by stimulating autophagy in aged triple transgenic mice. Biol Psychiatry. 2017;81:92–100.

    Article  Google Scholar 

  12. Chu J, Giannopoulos PF, Ceballos-Diaz C, Golde TE, Praticò D. Adeno-associated virus mediated brain delivery 5-lipoxygenase modulates AD-like phenotype of App mice. Mol Neurodegen. 2012;7:1

    Article  CAS  Google Scholar 

  13. 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's disease. Ann Neurol. 2012;72:442–54.

    Article  CAS  Google Scholar 

  14. Lauretti E, Iuliano L, Praticò D. Extra-virgin olive oil ameliorates cognition and neuropathology of the 3xTg mice: role of autophagy. Ann Clin Transl Neurol. 2017;4:564–74.

    Article  CAS  Google Scholar 

  15. Li J-G, Barrero C, Merali S, Praticò D. Genetic absence of ALOX5 protects from homocysteine-induced memory impairment, tau phosphorylation and synaptic pathology. Hum Mol Genet. 2017;26:1855–62.

    Article  CAS  Google Scholar 

  16. Giannopoulos PF, Chu J, Sperow M, Li JG, Yu WH, Kirby LG, et al. Pharmacologic inhibition of 5-Lipoxygenase improves memory, rescues synaptic dysfunction, and ameliorates tau pathology in a transgenic model of tauopathy. Biol Psychiatry. 2015;78:693–701.

    Article  CAS  Google Scholar 

  17. Di Meco A, Joshi YB, Lauretti E, Praticò D. Maternal dexamethasone exposure ameliorates cognition and tau pathology in the offspring of triple transgenic AD mice. Mol Psychiatry. 2016;21:403–10.

    Article  Google Scholar 

  18. Vagnozzi AN, Giannopoulos PF, Praticò D. The direct role of 5-lipoxygenase on tau pathology, synaptic integrity and cognition in a mouse model of tauopathy. Transl Psychiatry. 2017;7:1288.

    Article  Google Scholar 

  19. Giannopoulos PG, Praticò D. Alzheimer’s disease. In: Colin RM, Reddy V, editors. Diet nutrition in dementia and cognitive disorders. London, UK: Elsevier Publisher; 2015. pp. 13–21.

  20. Joshi Y, Praticò D. The 5-lipoxygenase pathway: oxidative and inflammatory contributions to the Alzheimer’s disease pathogenesis. Front Cell Neurosci. 2015;8:1–8.

    Article  Google Scholar 

  21. Joshi Y, Praticò D. Neuroinflammation and Alzheimer’s disease: lessons learned from 5-Lipoxygenase. Transl Neurosci. 2014;5:1–6.

  22. Succol F, Praticò D. A role for 12/15Lipoxygenase in the amyloid β precursor protein metabolism. J Neurochem. 2007;103:380–7.

    CAS  PubMed  Google Scholar 

  23. Chinnici C, Yao Y, Ding T, Funk C, Praticò D. Absence of 12/15 Lipoxygenase reduces brain oxidative stress in apolipoprotein E-deficient mice. Am J Pathol. 2005;167:1371–7.

    Article  CAS  Google Scholar 

  24. Puzzo D, Lee L, Palmeri A, Calabrese G, Arancio O. Behavioral assays with mouse models of Alzheimer’s disease: practical considerations and guidelines. Biochem Pharmacol. 2014;88:450–67.

    Article  CAS  Google Scholar 

  25. Whiting MD, Kokiko-Cochran ON. Assessment of cognitive function in the water maze task: maximizing data collection and analysis in animal models of brain injury. Methods Mol Biol. 2016;1462:553–71.

    Article  CAS  Google Scholar 

  26. Chu J, Zhuo JM, Praticò D. Transcriptional regulation of β-secreatse-1 by 12/15-Lipoxygenase results in enhanced amyloidogenesis and cognitive impairments. Ann Neurol. 2012;71:57–67.

    Article  CAS  Google Scholar 

  27. Wang JZ, Xia YY, Grundke-Iqbal I, Iqbal K. Abnormal hyperphosphorylation of tau: sites, regulation, and molecular mechanism of neurofibrillary degeneration. J Alzheimer Dis. 2013;33(suppl. 1):S123–S139.

    Google Scholar 

  28. Jan I, Park S, Cho JW, Yigitanli K, van Leyen K, Roth J. Genetic ablation and short-duration inhibition of lipoxygenase results in increased macroautophagy. Exp Cell Res. 2014;321:276–87.

    Article  Google Scholar 

  29. Morgan AH, Hammond VJ, Sakol-Nakatogawa M, Oshumi Y, Thomas CP, Blanchet F, et al. A novel role for 12/15-lipoxygenase in regulating autophagy. Redox Biol. 2015;4:40–47.

    Article  CAS  Google Scholar 

  30. Giannopoulos PF, Joshi YB, Praticò D. Novel lipid signaling pathways in Alzheimer’s disease pathogenesis. Biochem Pharmacol. 2014;88:560–4.

    Article  CAS  Google Scholar 

  31. Henstridge CM, Pickett E, Spires-Jones TL. Synaptic pathology: a shared mechanism in neurological disease. Ageing Res Rev. 2016;28:72–84.

    Article  CAS  Google Scholar 

  32. Ondrejcak T, Klyubin I, Hu NW, Barry AE, Cullen WK, Rowan MJ. Alzheimer’s disease amyloid beta-protein and synaptic function. Neuromolecular Med. 2010;12:13–26.

    Article  CAS  Google Scholar 

  33. Spangenberg EE, Green KN. Inflammation in Alzheimer’s disease: lessons learned from microglia-depletion models. Brain Behav Immun. 2017;61:1–11.

    Article  CAS  Google Scholar 

  34. Clayton KA, Van Enoo AA, Ikezu T. Alzheimer’s disease: The role of microglia in brain homeostasis and proteopathy. Front Neurosci. 2017;12:11–680.

    Google Scholar 

  35. González-Reyes RE, Nava-Mesa MO, Vargas-Sánchez K, Ariza-Salamanca D, Mora-Muñoz L. Involvement of astrocytes in Alzheimer’s disease from a neuroinflammatory and oxidative stress perspective. Front Mol Neurosci. 2017;10:427.

    Article  Google Scholar 

  36. Chun H, Lee CJ. Reactive astrocytes in Alzheimer’s disease: a double-edged sword. Neurosci Res. 2018;126:44–52.

    Article  CAS  Google Scholar 

  37. Zare-Shahabadi A, Masliah E, Johnson GV, Rezaei N. Autophagy in Alzheimer’s disease. Rev Neurosci. 2015;26:385–95.

    Article  Google Scholar 

Download references

Acknowledgements

Domenico Praticò is the Scott Richards North Star Charitable Foundation Chair for Alzheimer’s Research. This study was supported in part by grants from the Scott Richards North Star Charitable Foundation and the Wanda Simone Endowment for Neuroscience (to DP).

Author's contributions

JGL and DP designed the study; JGL and JC performed the experiments; JGL and DP analyzed the data and drafted the manuscript. All authors have discussed the results and seen the final version of the paper before submission.

Author information

Authors and Affiliations

  1. Alzheimer’s Center at Temple, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA

    Jian-Guo Li, Jin Chu & Domenico Praticò

Authors
  1. Jian-Guo Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jin Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Domenico Praticò
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Domenico Praticò.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, JG., Chu, J. & Praticò, D. Downregulation of autophagy by 12/15Lipoxygenase worsens the phenotype of an Alzheimer’s disease mouse model with plaques, tangles, and memory impairments. Mol Psychiatry 26, 604–613 (2021). https://doi.org/10.1038/s41380-018-0268-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-018-0268-1

This article is cited by

Search

Advanced search

Quick links