Cannabidiol Reverses Deficits in Hippocampal LTP in a Model of Alzheimer’s Disease

Abstract

Here we demonstrate for the first time that cannabidiol (CBD) acts to protect synaptic plasticity in an in vitro model of Alzheimer’s disease (AD). The non-psycho active component of Cannabis sativa, CBD has previously been shown to protect against the neurotoxic effects of beta amyloid peptide (Aβ) in cell culture and cognitive behavioural models of neurodegeneration. Hippocampal long-term potentiation (LTP) is an activity dependent increase in synaptic efficacy often used to study cellular mechanisms related to memory. Here we show that acute application of soluble oligomeric beta amyloid peptide (Aβ1–42) associated with AD, attenuates LTP in the CA1 region of hippocampal slices from C57Bl/6 mice. Application of CBD alone did not alter LTP, however pre-treatment of slices with CBD rescued the Aβ1–42 mediated deficit in LTP. We found that the neuroprotective effects of CBD were not reversed by WAY100635, ZM241385 or AM251, demonstrating a lack of involvement of 5HT1A, adenosine (A2A) or Cannabinoid type 1 (CB1) receptors respectively. However in the presence of the PPARγ antagonist GW9662 the neuroprotective effect of CBD was prevented. Our data suggests that this major component of Cannabis sativa, which lacks psychoactivity may have therapeutic potential for the treatment of AD.

This is a preview of subscription content, log in to check access.

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

References

  1. 1.

    Hardy J, Allsop D (1991) Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 12(10):383–388

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    Holtzman DM et al (2000) Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 97(6):2892–2897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Mc Donald JM et al (2010) The presence of sodium dodecyl sulphate-stable Aβ dimers is strongly associated with Alzheimer-type dementia. Brain 133(5):1328–1341

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Enya M et al (1999) Appearance of sodium dodecyl sulfate-stable amyloid beta-protein (Aβ) dimer in the cortex during aging. Am J Pathol 154(1):271–279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Roher AE et al (1996) Morphology and toxicity of Aβ-(1–42) dimer derived from neuritic and vascular amyloid deposits of Alzheimer’s disease. J Biol Chem 271(34):20631–20635

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Vigo-Pelfrey C et al (1993) Characterization of beta-amyloid peptide from human cerebrospinal fluid. J Neurochem 61(5):1965–1968

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Bliss TV, Collingridge GL, Morris RG (2014) Synaptic plasticity in health and disease: introduction and overview. Philos Trans R Soc Lond B Biol Sci 369(1633):20130129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Metais C et al (2014) Simvastatin treatment preserves synaptic plasticity in AβPPswe/PS1dE9 mice. J Alzheimers Dis 39(2):315–329

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Costello DA, O’Leary DM, Herron CE (2005) Agonists of peroxisome proliferator-activated receptor-gamma attenuate the Aβ-mediated impairment of LTP in the hippocampus in vitro. Neuropharmacology 49(3):359–366

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Lauren J et al (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 457(7233):1128–1132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Freir DB et al (2011) Interaction between prion protein and toxic amyloid beta assemblies can be therapeutically targeted at multiple sites. Nat Commun 2:336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Nicoll AJ et al (2013) Amyloid-beta nanotubes are associated with prion protein-dependent synaptotoxicity. Nat Commun 4:2416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Cheng D et al (2014) Chronic cannabidiol treatment improves social and object recognition in double transgenic APPswe/PS1∆E9 mice. Psychopharmacology 231(15):3009–3017

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Iuvone T et al (2004) Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells. J Neurochem 89(1):134–141

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Krishnan S, Cairns R, Howard R (2009) Cannabinoids for the treatment of dementia. Cochrane Database Syst Rev 2: CD007204

    Google Scholar 

  16. 16.

    Booz GW (2011) Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress. Free Radic Biol Med 51(5):1054–1061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Martin-Moreno AM et al (2011) Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer’s disease. Mol Pharmacol 79(6):964–973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Esposito G et al (2006) Cannabidiol inhibits inducible nitric oxide synthase protein expression and nitric oxide production in beta-amyloid stimulated PC12 neurons through p38 MAP kinase and NF-kappaB involvement. Neurosci Lett 399(1–2):91–95

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Esposito G et al (2011) Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement. PLoS ONE 6(12):e28668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Laprairie RB et al (2015) Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol 172(20):4790–4805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Vallee A et al (2017) Effects of cannabidiol interactions with Wnt/beta-catenin pathway and PPARγ on oxidative stress and neuroinflammation in Alzheimer’s disease. Acta Biochim Biophys Sin (Shanghai) 49(10):853–866

    Article  CAS  Google Scholar 

  22. 22.

    Ledgerwood CJ et al (2011) Cannabidiol inhibits synaptic transmission in rat hippocampal cultures and slices via multiple receptor pathways. Br J Pharmacol 162(1):286–294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Zanelati TV et al (2010) Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol 159(1):122–128

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Resstel LB et al (2009) 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol 156(1):181–188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Campos AC, Guimaraes FS (2008) Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology 199(2):223–230

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Ribeiro A et al (2012) Cannabidiol, a non-psychotropic plant-derived cannabinoid, decreases inflammation in a murine model of acute lung injury: role for the adenosine A(2A) receptor. Eur J Pharmacol 678(1–3):78–85

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Liou GI et al (2008) Mediation of cannabidiol anti-inflammation in the retina by equilibrative nucleoside transporter and A2A adenosine receptor. Invest Ophthalmol Vis Sci 49(12):5526–5531

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    O’Sullivan SE et al (2009) Time-dependent vascular actions of cannabidiol in the rat aorta. Eur J Pharmacol 612(1–3):61–68

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    McPartland JM, Glass M, Pertwee RG (2007) Meta-analysis of cannabinoid ligand binding affinity and receptor distribution: interspecies differences. Br J Pharmacol 152(5):583–593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Thomas A et al (2007) Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol 150(5):613–623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Bisogno T et al (2001) Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 134(4):845–852

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Carrier EJ, Auchampach JA, Hillard CJ (2006) Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci USA 103(20):7895–7900

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Forster EA et al (1995) A pharmacological profile of the selective silent 5-HT1A receptor antagonist, WAY-100635. Eur J Pharmacol 281(1):81–88

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Dall’Igna OP et al (2003) Neuroprotection by caffeine and adenosine A2A receptor blockade of beta-amyloid neurotoxicity. Br J Pharmacol 138(7):1207–1209

    Article  CAS  PubMed  Google Scholar 

  35. 35.

    Leesnitzer LM et al (2002) Functional consequences of cysteine modification in the ligand binding sites of peroxisome proliferator activated receptors by GW9662. Biochemistry 41(21):6640–6650

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    Ryan D et al (2009) Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels. J Neurosci 29(7):2053–2063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Shankar GM et al (2007) Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 27(11):2866–2875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Pugliese AM, Passani MB, Corradetti R (1998) Effect of the selective 5-HT1A receptor antagonist WAY 100635 on the inhibition of e.p.s.ps produced by 5-HT in the CA1 region of rat hippocampal slices. Br J Pharmacol 124(1):93–100

    Article  CAS  PubMed  Google Scholar 

  39. 39.

    Thomas BF et al (1998) Comparative receptor binding analyses of cannabinoid agonists and antagonists. J Pharmacol Exp Ther 285(1):285–292

    CAS  PubMed  Google Scholar 

  40. 40.

    Hoffman AF et al (2010) Control of cannabinoid CB1 receptor function on glutamate axon terminals by endogenous adenosine acting at A1 receptors. J Neurosci 30(2):545–555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Pertwee RG (2008) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: ∆9-tetrahydrocannabinol, cannabidiol and ∆9-tetrahydrocannabivarin. Br J Pharmacol 153(2):199–215

    Article  CAS  PubMed  Google Scholar 

  42. 42.

    Martinez-Pinilla E et al (2017) Binding and signaling studies disclose a potential allosteric site for cannabidiol in cannabinoid CB2 receptors. Front Pharmacol 8:744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    de Mendonça A, Ribeiro JA (2001) Adenosine and synaptic plasticity. Drug Dev Res 52(1–2):283–290

    Article  Google Scholar 

  44. 44.

    Rombo DM et al (2015) Synaptic mechanisms of adenosine A2A receptor-mediated hyperexcitability in the hippocampus. Hippocampus 25(5):566–580

    Article  CAS  PubMed  Google Scholar 

  45. 45.

    Hasko G, Cronstein BN (2004) Adenosine: an endogenous regulator of innate immunity. Trends Immunol 25(1):33–39

    Article  CAS  PubMed  Google Scholar 

  46. 46.

    Castillo A et al (2010) The neuroprotective effect of cannabidiol in an in vitro model of newborn hypoxic-ischemic brain damage in mice is mediated by CB2 and adenosine receptors. Neurobiol Dis 37(2):434–440

    Article  CAS  PubMed  Google Scholar 

  47. 47.

    Slanina KA, Roberto M, Schweitzer P (2005) Endocannabinoids restrict hippocampal long-term potentiation via CB1. Neuropharmacology 49(5):660–668

    Article  CAS  PubMed  Google Scholar 

  48. 48.

    Karl T et al (2012) The therapeutic potential of the endocannabinoid system for Alzheimer’s disease. Expert Opin Ther Targets 16(4):407–420

    Article  CAS  PubMed  Google Scholar 

  49. 49.

    Mazzola C, Micale V, Drago F (2003) Amnesia induced by beta-amyloid fragments is counteracted by cannabinoid CB1 receptor blockade. Eur J Pharmacol 477(3):219–225

    Article  CAS  PubMed  Google Scholar 

  50. 50.

    Heneka MT, Landreth GE (2007) PPARs in the brain. Biochim Biophys Acta 1771(8):1031–1045

    Article  CAS  PubMed  Google Scholar 

  51. 51.

    Bouhlel MA et al (2007) PPARγ activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab 6(2):137–143

    Article  CAS  PubMed  Google Scholar 

  52. 52.

    Jo J et al (2011) Aβ(1–42) inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3β. Nat Neurosci 14(5):545–547

    Article  CAS  PubMed  Google Scholar 

  53. 53.

    Peineau S et al (2007) LTP inhibits LTD in the hippocampus via regulation of GSK3β. Neuron 53(5):703–717

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    da Silva VK et al (2014) Cannabidiol normalizes caspase 3, synaptophysin, and mitochondrial fission protein DNM1L expression levels in rats with brain iron overload: implications for neuroprotection. Mol Neurobiol 49(1):222–233

    Article  CAS  PubMed  Google Scholar 

  55. 55.

    Fagherazzi EV et al (2012) Memory-rescuing effects of cannabidiol in an animal model of cognitive impairment relevant to neurodegenerative disorders. Psychopharmacology 219(4):1133–1140

    Article  CAS  PubMed  Google Scholar 

  56. 56.

    Esposito G et al (2006) The marijuana component cannabidiol inhibits beta-amyloid-induced tau protein hyperphosphorylation through Wnt/beta-catenin pathway rescue in PC12 cells. J Mol Med (Berl) 84(3):253–258

    Article  CAS  Google Scholar 

  57. 57.

    Cabrero A, Laguna JC, Vazquez M (2002) Peroxisome proliferator-activated receptors and the control of inflammation. Curr Drug Targets Inflamm Allergy 1(3):243–248

    Article  CAS  PubMed  Google Scholar 

  58. 58.

    Inestrosa NC et al (2005) Peroxisome proliferator-activated receptor gamma is expressed in hippocampal neurons and its activation prevents beta-amyloid neurodegeneration: role of Wnt signaling. Exp Cell Res 304(1):91–104

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Caroline E. Herron.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hughes, B., Herron, C.E. Cannabidiol Reverses Deficits in Hippocampal LTP in a Model of Alzheimer’s Disease. Neurochem Res 44, 703–713 (2019). https://doi.org/10.1007/s11064-018-2513-z

Download citation

Keywords

  • Cannabidiol
  • Alzheimer’s disease
  • Long-term potentiation
  • PPARγ
  • Beta amyloid peptide
  • 5HT1A
  • Adenosine A2A
  • CB1R