Skip to main content

Advertisement

SpringerLink
Log in

Alleviation of Neuropathology by Inhibition of Monoacylglycerol Lipase in APP Transgenic Mice Lacking CB2 Receptors

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Inhibition of monoacylglycerol lipase (MAGL), the primary enzyme that hydrolyzes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, produces profound anti-inflammatory and neuroprotective effects and improves synaptic and cognitive functions in animal models of Alzheimer’s disease (AD). However, the molecular mechanisms underlying the beneficial effects produced by inhibition of 2-AG metabolism are still not clear. The cannabinoid receptor type 2 (CB2R) has been thought to be a therapeutic target for AD. Here, we provide evidence, however, that CB2R does not play a role in ameliorating AD neuropathology produced by inactivation of MAGL in 5XFAD APP transgenic mice, an animal model of AD. We observed that expression of APP and β-secretase as well as production of total Aβ and Aβ42 were significantly reduced in APP transgenic mice lacking CB2R (TG-CB2-KO) treated with JZL184, a selective and potent inhibitor for MAGL. Inactivation of MAGL also alleviated neuroinflammation and neurodegeneration in TG-CB2-KO mice. Importantly, TG-CB2-KO mice treated with JZL184 still exhibited improvements in spatial learning and memory. In addition, MAGL inhibition prevented deterioration in expression of important synaptic proteins in TG-CB2-KO mice. Our results suggest that CB2R is not required in ameliorating neuropathology and preventing cognitive decline by inhibition of 2-AG metabolism in AD model animals.

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. Chen X, Zhang J, Chen C (2011) Endocannabinoid 2-arachidonoylglycerol protects neurons against beta-amyloid insults. Neuroscience 178:159–168. doi:10.1016/j.neuroscience.2011.01.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Du H, Chen X, Zhang J, Chen C (2011) Inhibition of COX-2 expression by endocannabinoid 2-arachidonoylglycerol is mediated via PPAR-gamma. Br J Pharmacol 163:1533–1549. doi:10.1111/j.1476-5381.2011.01444.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhang J, Chen C (2008) Endocannabinoid 2-arachidonoylglycerol protects neurons by limiting COX-2 elevation. J Biol Chem 283:22601–22611. doi:10.1074/jbc.M800524200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Xu JY, Chen C (2015) Endocannabinoids in synaptic plasticity and neuroprotection. Neuroscientist 21:152–168. doi:10.1177/1073858414524632

    Article  CAS  PubMed  Google Scholar 

  5. Shohami E, Cohen-Yeshurun A, Magid L, Algali M, Mechoulam R (2011) Endocannabinoids and traumatic brain injury. Br J Pharmacol 163:1402–1410. doi:10.1111/j.1476-5381.2011.01343.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sugiura T, Kishimoto S, Oka S, Gokoh M (2006) Biochemistry, pharmacology and physiology of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand. Prog Lipid Res 45:405–446. doi:10.1016/j.plipres.2006.03.003

    Article  CAS  PubMed  Google Scholar 

  7. Hermanson DJ, Gamble-George JC, Marnett LJ, Patel S (2014) Substrate-selective COX-2 inhibition as a novel strategy for therapeutic endocannabinoid augmentation. Trends Pharmacol Sci 35:358–367. doi:10.1016/j.tips.2014.04.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Blankman JL, Simon GM, Cravatt BF (2007) A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem Biol 14:1347–1356. doi:10.1016/j.chembiol.2007.11.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Nomura DK, Morrison BE, Blankman JL, Long JZ, Kinsey SG, Marcondes MC, Ward AM, Hahn YK et al (2011) Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science 334:809–813. doi:10.1126/science.1209200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hein AM, O'Banion MK (2009) Neuroinflammation and memory: the role of prostaglandins. Mol Neurobiol 40:15–32. doi:10.1007/s12035-009-8066-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Salmon JA, Higgs GA (1987) Prostaglandins and leukotrienes as inflammatory mediators. Br Med Bull 43:285–296

    Article  CAS  PubMed  Google Scholar 

  12. Chen C (2016) Endocannabinoid metabolism in neurodegenerative diseases. Neuroimmunol Neuroinflamm 3:268–270. doi:10.20517/2347-8659.2016.46

    Article  PubMed  PubMed Central  Google Scholar 

  13. Chen R, Zhang J, Wu Y, Wang D, Feng G, Tang YP, Teng Z, Chen C (2012) Monoacylglycerol lipase is a therapeutic target for Alzheimer’s disease. Cell Rep 2:1329–1339. doi:10.1016/j.celrep.2012.09.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Piro JR, Benjamin DI, Duerr JM, Pi Y, Gonzales C, Wood KM, Schwartz JW, Nomura DK et al (2012) A dysregulated endocannabinoid-eicosanoid network supports pathogenesis in a mouse model of Alzheimer’s disease. Cell Rep 1:617–623. doi:10.1016/j.celrep.2012.05.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Atwood BK, Straiker A, Mackie K (2012) CB(2): therapeutic target-in-waiting. Prog Neuro-Psychopharmacol Biol Psychiatry 38:16–20. doi:10.1016/j.pnpbp.2011.12.001

    Article  CAS  Google Scholar 

  16. Ashton JC, Glass M (2007) The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration. Curr Neuropharmacol 5:73–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cassano T, Calcagnini S, Pace L, De Marco F, Romano A, Gaetani S (2017) Cannabinoid receptor 2 signaling in neurodegenerative disorders: from pathogenesis to a promising therapeutic target. Front Neurosci 11:30. doi:10.3389/fnins.2017.00030

    Article  PubMed  PubMed Central  Google Scholar 

  18. Brusco A, Tagliaferro P, Saez T, Onaivi ES (2008) Postsynaptic localization of CB2 cannabinoid receptors in the rat hippocampus. Synapse 62:944–949. doi:10.1002/syn.20569

    Article  CAS  PubMed  Google Scholar 

  19. den Boon FS, Chameau P, Schaafsma-Zhao Q, van Aken W, Bari M, Oddi S, Kruse CG, Maccarrone M et al (2012) Excitability of prefrontal cortical pyramidal neurons is modulated by activation of intracellular type-2 cannabinoid receptors. Proc Natl Acad Sci U S A 109:3534–3539. doi:10.1073/pnas.1118167109

    Article  Google Scholar 

  20. Gong JP, Onaivi ES, Ishiguro H, Liu QR, Tagliaferro PA, Brusco A, Uhl GR (2006) Cannabinoid CB2 receptors: Immunohistochemical localization in rat brain. Brain Res 1071:10–23. doi:10.1016/j.brainres.2005.11.035

    Article  CAS  PubMed  Google Scholar 

  21. Li Y, Kim J (2015) Neuronal expression of CB2 cannabinoid receptor mRNAs in the mouse hippocampus. Neuroscience 311:253–267. doi:10.1016/j.neuroscience.2015.10.041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Stempel AV, Stumpf A, Zhang HY, Ozdogan T, Pannasch U, Theis AK, Otte DM, Wojtalla A et al (2016) Cannabinoid type 2 receptors mediate a cell type-specific plasticity in the hippocampus. Neuron 90:795–809. doi:10.1016/j.neuron.2016.03.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, Stella N, Makriyannis A et al (2005) Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310:329–332. doi:10.1126/science.1115740

    Article  PubMed  Google Scholar 

  24. Zhang HY, Gao M, Liu QR, Bi GH, Li X, Yang HJ, Gardner EL, Wu J et al (2014) Cannabinoid CB2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice. Proc Natl Acad Sci U S A 111:E5007–E5015. doi:10.1073/pnas.1413210111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ramirez BG, Blazquez C, Gomez del Pulgar T, Guzman M, de Ceballos ML (2005) Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci 25:1904–1913. doi:10.1523/jneurosci.4540-04.2005

    Article  CAS  PubMed  Google Scholar 

  26. Solas M, Francis PT, Franco R, Ramirez MJ (2013) CB2 receptor and amyloid pathology in frontal cortex of Alzheimer’s disease patients. Neurobiol Aging 34:805–808. doi:10.1016/j.neurobiolaging.2012.06.005

    Article  CAS  PubMed  Google Scholar 

  27. Aso E, Andres-Benito P, Carmona M, Maldonado R, Ferrer I (2016) Cannabinoid receptor 2 participates in amyloid-beta processing in a mouse model of Alzheimer’s disease but plays a minor role in the therapeutic properties of a cannabis-based medicine. J Alzheimers Dis 51:489–500. doi:10.3233/jad-150913

    Article  CAS  PubMed  Google Scholar 

  28. Koppel J, Vingtdeux V, Marambaud P, d'Abramo C, Jimenez H, Stauber M, Friedman R, Davies P (2014) CB2 receptor deficiency increases amyloid pathology and alters tau processing in a transgenic mouse model of Alzheimer’s disease. Mol Med 20:29–36. doi:10.2119/molmed.2013.00140.revised

    PubMed  PubMed Central  Google Scholar 

  29. Schmole AC, Lundt R, Ternes S, Albayram O, Ulas T, Schultze JL, Bano D, Nicotera P et al (2015) Cannabinoid receptor 2 deficiency results in reduced neuroinflammation in an Alzheimer’s disease mouse model. Neurobiol Aging 36:710–719. doi:10.1016/j.neurobiolaging.2014.09.019

    Article  PubMed  Google Scholar 

  30. Aso E, Ferrer I (2016) CB2 cannabinoid receptor as potential target against Alzheimer’s disease. Front Neurosci 10:243. doi:10.3389/fnins.2016.00243

    Article  PubMed  PubMed Central  Google Scholar 

  31. Zhang J, Hu M, Teng Z, Tang YP, Chen C (2014) Synaptic and cognitive improvements by inhibition of 2-AG metabolism are through upregulation of microRNA-188-3p in a mouse model of Alzheimer’s disease. J Neurosci 34:14919–14933. doi:10.1523/jneurosci.1165-14.2014

    Article  PubMed  PubMed Central  Google Scholar 

  32. Pihlaja R, Takkinen J, Eskola O, Vasara J, Lopez-Picon FR, Haaparanta-Solin M, Rinne JO (2015) Monoacylglycerol lipase inhibitor JZL184 reduces neuroinflammatory response in APdE9 mice and in adult mouse glial cells. J Neuroinflammation 12:81. doi:10.1186/s12974-015-0305-9

    Article  PubMed  PubMed Central  Google Scholar 

  33. Bisogno T, Oddi S, Piccoli A, Fazio D, Maccarrone M (2016) Type-2 cannabinoid receptors in neurodegeneration. Pharmacol Res 111:721–730. doi:10.1016/j.phrs.2016.07.021

    Article  CAS  PubMed  Google Scholar 

  34. Pan B, Wang W, Zhong P, Blankman JL, Cravatt BF, Liu QS (2011) Alterations of endocannabinoid signaling, synaptic plasticity, learning, and memory in monoacylglycerol lipase knock-out mice. J Neurosci 31:13420–13430. doi:10.1523/jneurosci.2075-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791. doi:10.1126/science.1074069

    Article  CAS  PubMed  Google Scholar 

  36. Long JZ, Li W, Booker L, Burston JJ, Kinsey SG, Schlosburg JE, Pavon FJ, Serrano AM et al (2009) Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat Chem Biol 5:37–44. doi:10.1038/nchembio.129

    Article  CAS  PubMed  Google Scholar 

  37. Long JZ, Nomura DK, Cravatt BF (2009) Characterization of monoacylglycerol lipase inhibition reveals differences in central and peripheral endocannabinoid metabolism. Chem Biol 16:744–753. doi:10.1016/j.chembiol.2009.05.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Panikashvili D, Simeonidou C, Ben-Shabat S, Hanus L, Breuer A, Mechoulam R, Shohami E (2001) An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 413:527–531. doi:10.1038/35097089

    Article  CAS  PubMed  Google Scholar 

  39. Chen C (2015) Homeostatic regulation of brain functions by endocannabinoid signaling. Neural Regen Res 10:691–692. doi:10.4103/1673-5374.156947

    Article  PubMed  PubMed Central  Google Scholar 

  40. Song Y, Zhang J, Chen C (2015) Fine-tuning of synaptic upscaling at excitatory synapses by endocannabinoid signaling is mediated via the CB1 receptor. Sci Rep 5:16257. doi:10.1038/srep16257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Marchalant Y, Brothers HM, Norman GJ, Karelina K, DeVries AC, Wenk GL (2009) Cannabinoids attenuate the effects of aging upon neuroinflammation and neurogenesis. Neurobiol Dis 34:300–307

    Article  CAS  PubMed  Google Scholar 

  42. Petrosino S, Schiano Moriello A, Cerrato S, Fusco M, Puigdemont A, De Petrocellis L, Di Marzo V (2016) The anti-inflammatory mediator palmitoylethanolamide enhances the levels of 2-arachidonoyl-glycerol and potentiates its actions at TRPV1 cation channels. Br J Pharmacol 173:1154–1162. doi:10.1111/bph.13084

    Article  CAS  PubMed  Google Scholar 

  43. O'Sullivan SE (2016) An update on PPAR activation by cannabinoids. Br J Pharmacol 173:1899–1910. doi:10.1111/bph.13497

    Article  PubMed  PubMed Central  Google Scholar 

  44. Bensinger SJ, Tontonoz P (2008) Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature 454:470–477. doi:10.1038/nature07202

    Article  CAS  PubMed  Google Scholar 

  45. Rockwell CE, Snider NT, Thompson JT, Vanden Heuvel JP, Kaminski NE (2006) Interleukin-2 suppression by 2-arachidonyl glycerol is mediated through peroxisome proliferator-activated receptor gamma independently of cannabinoid receptors 1 and 2. Mol Pharmacol 70:101–111. doi:10.1124/mol.105.019117

    CAS  PubMed  Google Scholar 

  46. Chen R, Zhang J, Fan N, Teng ZQ, Wu Y, Yang H, Tang YP, Sun H et al (2013) Delta9-THC-caused synaptic and memory impairments are mediated through COX-2 signaling. Cell 155:1154–1165. doi:10.1016/j.cell.2013.10.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhang J, Teng Z, Song Y, Hu M, Chen C (2015) Inhibition of monoacylglycerol lipase prevents chronic traumatic encephalopathy-like neuropathology in a mouse model of repetitive mild closed head injury. J Cereb Blood Flow Metab 35:443–453. doi:10.1038/jcbfm.2014.216

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Institutes of Health Grant R01 NS076815. We thank the National Institutes of Health Mental Health Institute Chemical Synthesis and Drug Supply Program for providing JZL184.

Author information

Authors and Affiliations

  1. Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite D, New Orleans, LA, 70112, USA

    Jian Zhang & Chu Chen

  2. Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA

    Chu Chen

Authors
  1. Jian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

C.C. and J.Z. designed and performed the experiment. C.C. and J.Z. analyzed the data. C.C. wrote the manuscript. All authors reviewed the manuscript.

Corresponding author

Correspondence to Chu Chen.

Ethics declarations

Disclosure/Conflict of Interest

The authors declare 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

Zhang, J., Chen, C. Alleviation of Neuropathology by Inhibition of Monoacylglycerol Lipase in APP Transgenic Mice Lacking CB2 Receptors. Mol Neurobiol 55, 4802–4810 (2018). https://doi.org/10.1007/s12035-017-0689-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-017-0689-x

Keywords

Search

Navigation