Chronic cannabidiol treatment improves social and object recognition in double transgenic APPswe/PS1∆E9 mice
- 1.4k Downloads
Patients suffering from Alzheimer’s disease (AD) exhibit a decline in cognitive abilities including an inability to recognise familiar faces. Hallmark pathological changes in AD include the aggregation of amyloid-β (Aβ), tau protein hyperphosphorylation as well as pronounced neurodegeneration, neuroinflammation, neurotoxicity and oxidative damage.
The non-psychoactive phytocannabinoid cannabidiol (CBD) exerts neuroprotective, anti-oxidant and anti-inflammatory effects and promotes neurogenesis. CBD also reverses Aβ-induced spatial memory deficits in rodents.
Materials and methods
Thus we determined the therapeutic-like effects of chronic CBD treatment (20 mg/kg, daily intraperitoneal injections for 3 weeks) on the APPswe/PS1∆E9 (APPxPS1) transgenic mouse model for AD in a number of cognitive tests, including the social preference test, the novel object recognition task and the fear conditioning paradigm. We also analysed the impact of CBD on anxiety behaviours in the elevated plus maze.
Vehicle-treated APPxPS1 mice demonstrated impairments in social recognition and novel object recognition compared to wild type-like mice. Chronic CBD treatment reversed these cognitive deficits in APPxPS1 mice without affecting anxiety-related behaviours.
This is the first study to investigate the effect of chronic CBD treatment on cognition in an AD transgenic mouse model. Our findings suggest that CBD may have therapeutic potential for specific cognitive impairments associated with AD.
KeywordsAlzheimer’s disease Novel therapeutic Cannabidiol Transgenic APPswe/PS1∆E9 mice Cognition Behaviour Social recognition memory Object recognition memory
TK is supported by the Schizophrenia Research Institute utilising infrastructure funding from NSW Ministry of Health, the Motor Neuron Disease Research Institute of Australia (Mick Rodger Benalla MND Research Grant) and a career development fellowship (1045643) from the National Health and Medical Research Council (NHMRC). BG is supported by a Fellowship from the Australian Research Council (FT0991986) and is an honorary NHMRC Senior Research Fellow (630445). BG and TK are also supported by a NHMRC project grant (1003886). DC received an Australian Postgraduate Award scholarship from the University of New South Wales and a supplementary scholarship provided by Neuroscience Research Australia. We thank Jerry Tanda for the critical comments on the manuscript, the staff of the Australian BioResources and Adam Bryan at Neuroscience Research Australia for taking care of our test mice.
- Campos AC, Ortega Z, Palazuelos J, Fogaca MV, Aguiar DC, Diaz-Alonso J, Ortega-Gutierrez S, Vazquez-Villa H, Moreira FA, Guzman M, Galve-Roperh I, Guimaraes FS (2013) The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system. Int J Neuropsychopharmacol 16:1407–19PubMedCrossRefGoogle Scholar
- Deiana S, Watanabe A, Yamasaki Y, Amada N, Arthur M, Fleming S, Woodcock H, Dorward P, Pigliacampo B, Close S, Platt B, Riedel G (2012) Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Delta(9)-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour. Psychopharmacol (Berl) 219:859–73CrossRefGoogle Scholar
- Donkin JJ, Stukas S, Hirsch-Reinshagen V, Namjoshi D, Wilkinson A, May S, Chan J, Fan J, Collins J, Wellington CL (2010) ATP-binding cassette transporter A1 mediates the beneficial effects of the liver X receptor agonist GW3965 on object recognition memory and amyloid burden in amyloid precursor protein/presenilin 1 mice. J Biol Chem 285:34144–54PubMedCrossRefPubMedCentralGoogle Scholar
- Hallak JE, Dursun SM, Bosi DC, de Macedo LR, Machado-de-Sousa JP, Abrao J, Crippa JA, McGuire P, Krystal JH, Baker GB, Zuardi AW (2011) The interplay of cannabinoid and NMDA glutamate receptor systems in humans: preliminary evidence of interactive effects of cannabidiol and ketamine in healthy human subjects. Prog Neuropsychopharmacol Biol Psychiatry 35:198–202PubMedCrossRefGoogle Scholar
- Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, Copeland NG, Lee MK, Younkin LH, Wagner SL, Younkin SG, Borchelt DR (2004a) Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 13:159–70PubMedCrossRefGoogle Scholar
- Koppel J, Davies P (2008) Targeting the endocannabinoid system in Alzheimer’s disease. J Alzheimer’s Dis JAD 15:495–504Google Scholar
- Krishnan S, Cairns R, Howard R (2009) Cannabinoids for the treatment of dementia. Cochrane Database Syst Rev: (2). doi: 10.1002/14651858.CD007204.pub2
- Pratico D, Sung S (2004) Lipid peroxidation and oxidative imbalance: early functional events in Alzheimer’s disease. J Alzheimer’s Dis JAD 6:171–5Google Scholar
- Scholtzova H, Wadghiri YZ, Douadi M, Sigurdsson EM, Li YS, Quartermain D, Banerjee P, Wisniewski T (2008) Memantine leads to behavioral improvement and amyloid reduction in Alzheimer’s-disease-model transgenic mice shown as by micromagnetic resonance imaging. J Neurosci Res 86:2784–91PubMedCrossRefPubMedCentralGoogle Scholar
- Wolf SA, Bick-Sander A, Fabel K, Leal-Galicia P, Tauber S, Ramirez-Rodriguez G, Muller A, Melnik A, Waltinger TP, Ullrich O, Kempermann G (2010) Cannabinoid receptor CB1 mediates baseline and activity-induced survival of new neurons in adult hippocampal neurogenesis. Cell Commun signal CCS 8:12CrossRefGoogle Scholar