title: CB2 cannabinoid receptor agonist ameliorates Alzheimer-like phenotype in AβPP/PS1 mice.
abstract: The specific CB2 cannabinoid receptor agonist JWH-133 induced cognitive improvement in double AβPP/PS1 transgenic mice, a genetic model of Alzheimer's disease. This effect was more pronounced when administered at the pre-symptomatic rather than the early symptomatic stage. The cognitive improvement was associated with decreased microglial reactivity and reduced expression of pro-inflammatory cytokines IL-1β, IL-6, TNFα, and IFNγ. In addition, JWH-133 reduced the expression of active p38 and SAPK/JNK, increased the expression of inactive GSK3β, and lowered tau hyperphosphorylation at Thr181 in the vicinity of amyloid-β plaques. Moreover, JWH-133 produced a decrease in the expression of hydroxynonenal adducts, and enhanced the expression of SOD1 and SOD2 around plaques. In contrast, the chronic treatment with JWH-133 failed to modify the amyloid-β production or deposition in cortex and hippocampus. In conclusion, the present study lends support to the idea that stimulation of CB2 receptors ameliorates several altered parameters in Alzheimer's disease such as impaired memory and learning, neuroinflammation, oxidative stress damage and oxidative stress responses, selected tau kinases, and tau hyperphosphorylation around plaques.
authors.affiliation: Institut de Neuropatologia, Servei d'Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain. aso@bellvitgehospital.cat
authors.forename: Ester
authors.initials: E
authors.lastname: Aso
authors.forename: Salvador
authors.initials: S
authors.lastname: Juvés
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.forename: Isidro
authors.initials: I
authors.lastname: Ferrer
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D063386:Cannabinoid Receptor Agonists / Q000627:therapeutic use*; D002186:Cannabinoids / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000502:physiology; D058225:Plaque, Amyloid / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics*; D011597:Psychomotor Performance / Q000502:physiology; D012313:RNA / Q000096:biosynthesis; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000096:biosynthesis; D021641:Recognition, Psychology / Q000502:physiology; D016708:Synaptophysin / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D016207:Cytokines; D053764:Presenilin-1; D043885:Receptor, Cannabinoid, CB2; D016708:Synaptophysin; D016875:tau Proteins; D012313:RNA; D038362:Glycogen Synthase Kinase 3; C080888:tau-protein kinase; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC