title: Prolonged oral cannabinoid administration prevents neuroinflammation, lowers β-amyloid levels and improves cognitive performance in Tg APP 2576 mice.
abstract: BACKGROUND
  Alzheimer's disease (AD) brain shows an ongoing inflammatory condition and non-steroidal anti-inflammatories diminish the risk of suffering the neurologic disease. Cannabinoids are neuroprotective and anti-inflammatory agents with therapeutic potential.
  
  
  METHODS
  We have studied the effects of prolonged oral administration of transgenic amyloid precursor protein (APP) mice with two pharmacologically different cannabinoids (WIN 55,212-2 and JWH-133, 0.2 mg/kg/day in the drinking water during 4 months) on inflammatory and cognitive parameters, and on ¹⁸F-fluoro-deoxyglucose (¹⁸FDG) uptake by positron emission tomography (PET).
  
  
  RESULTS
  Novel object recognition was significantly reduced in 11 month old Tg APP mice and 4 month administration of JWH was able to normalize this cognitive deficit, although WIN was ineffective. Wild type mice cognitive performance was unaltered by cannabinoid administration. Tg APP mice showed decreased ¹⁸FDG uptake in hippocampus and cortical regions, which was counteracted by oral JWH treatment. Hippocampal GFAP immunoreactivity and cortical protein expression was unaffected by genotype or treatment. In contrast, the density of Iba1 positive microglia was increased in Tg APP mice, and normalized following JWH chronic treatment. Both cannabinoids were effective at reducing the enhancement of COX-2 protein levels and TNF-α mRNA expression found in the AD model. Increased cortical β-amyloid (Aβ) levels were significantly reduced in the mouse model by both cannabinoids. Noteworthy both cannabinoids enhanced Aβ transport across choroid plexus cells in vitro.
  
  
  CONCLUSIONS
  In summary we have shown that chronically administered cannabinoid showed marked beneficial effects concomitant with inflammation reduction and increased Aβ clearance.
authors.affiliation: Neurodenegeration Group, Dept. of Cellular, Molecular and Developmental Neurobiology, Instituto Cajal, CSIC, Doctor Arce 37, Madrid 28002, Spain.
authors.forename: Ana María
authors.initials: AM
authors.lastname: Martín-Moreno
authors.forename: Begoña
authors.initials: B
authors.lastname: Brera
authors.forename: Carlos
authors.initials: C
authors.lastname: Spuch
authors.forename: Eva
authors.initials: E
authors.lastname: Carro
authors.forename: Luis
authors.initials: L
authors.lastname: García-García
authors.forename: Mercedes
authors.initials: M
authors.lastname: Delgado
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Pozo
authors.forename: Nadia G
authors.initials: NG
authors.lastname: Innamorato
authors.forename: Antonio
authors.initials: A
authors.lastname: Cuadrado
authors.forename: María L
authors.initials: ML
authors.lastname: de Ceballos
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D048588:Benzoxazines / Q000008:administration & dosage; D002186:Cannabinoids / Q000008:administration & dosage*; D002831:Choroid Plexus / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000000981:diagnostic imaging / Q000209:etiology / Q000517:prevention & control*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000000981:diagnostic imaging / Q000209:etiology / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D009025:Morpholines / Q000008:administration & dosage; D009281:Naphthalenes / Q000008:administration & dosage; D049268:Positron-Emission Tomography; D012333:RNA, Messenger / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D012333:RNA, Messenger; D043885:Receptor, Cannabinoid, CB2; D019788:Fluorodeoxyglucose F18; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC