title: CB1 agonist ACEA protects neurons and reduces the cognitive impairment of AβPP/PS1 mice.
abstract: The present study shows that chronic administration of the cannabinoid receptor type 1 (CB1) receptor agonist arachidonyl-2-chloroethylamide (ACEA) at pre-symptomatic or at early symptomatic stages, at a non-amnesic dose, reduces the cognitive impairment observed in double AβPP(swe)/PS1(1dE9) transgenic mice from 6 months of age onwards. ACEA has no effect on amyloid-β (Aβ) production, aggregation, or clearance. However, ACEA reduces the cytotoxic effect of Aβ42 oligomers in primary cultures of cortical neurons, and reverses Aβ-induced dephosphorylation of glycogen synthase kinase-3β (GSK3β) in vitro and in vivo. Reduced activity of GSK3β in ACEA-treated mice is further supported by the reduced amount of phospho-tau (Thr181) in neuritic processes around Aβ plaques. In addition, ACEA-treated mice show decreased astroglial response in the vicinity of Aβ plaques and decreased expression of the pro-inflammatory cytokine interferon-γ in astrocytes when compared with age-matched vehicle-treated transgenic mice. Our present results show a beneficial effect of ACEA at both the neuronal, mediated at least in part by GSK3β inhibition, and glial levels, resulting in a reduction of reactive astrocytes and lower expression of interferon-γ. As a consequence, targeting the CB1 receptor could offer a versatile approach for the treatment of Alzheimer's disease.
authors.affiliation: Institut de Neuropatologia, Servei d'Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain. aso@bellvitgehospital.cat
authors.forename: Ester
authors.initials: E
authors.lastname: Aso
authors.forename: Ernest
authors.initials: E
authors.lastname: Palomer
authors.forename: Salvador
authors.initials: S
authors.lastname: Juvés
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Muñoz
authors.forename: Isidro
authors.initials: I
authors.lastname: Ferrer
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000235:genetics*; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy / Q000517:prevention & control; D004195:Disease Models, Animal; D005260:Female; D005911:Gliosis / Q000517:prevention & control; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000166:cytology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011247:Pregnancy; D053764:Presenilin-1 / Q000235:genetics*; D061251:Primary Cell Culture; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D001095:Arachidonic Acids; D018696:Neuroprotective Agents; D053764:Presenilin-1; D043884:Receptor, Cannabinoid, CB1; C119325:arachidonyl-2-chloroethylamide; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3