CB1 agonist ACEA protects neurons and reduces the cognitive impairment of AβPP/PS1 mice

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• dc.contributor.author Aso Pérez, Esterca
• dc.contributor.author Palomer, Ernestca
• dc.contributor.author Juvés, Salvadorca
• dc.contributor.author Maldonado, Rafael, 1961-ca
• dc.contributor.author Muñoz López, Francisco José, 1964-ca
• dc.contributor.author Ferrer, Isidreca
• dc.date.accessioned 2015-03-26T08:21:11Z
• dc.date.available 2015-03-26T08:21:11Z
• dc.date.issued 2012ca
• dc.description.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.
• dc.description.sponsorship This study was supported by grants from the Spanish Ministry of Health (FIS PI08/0582 to IF; PI07/0593 to FJM), ERA-NET-NEURON (IF), Agrupació Mútua Foundation (XVII Award in the Elderly Field, to IF) and Mutua Madrileña Foundation (IF)
• dc.format.mimetype application/pdfca
• dc.identifier.citation Aso E, Palomer E, Juvés S, Maldonado R, Muñoz FJ, Ferrer I. CB1 agonist ACEA protects neurons and reduces the cognitive impairment of AβPP/PS1 mice. J Alzheimers Dis. 2012;30(2):439-59. DOI: 10.3233/JAD-2012-111862ca
• dc.identifier.doi http://dx.doi.org/10.3233/JAD-2012-111862
• dc.identifier.issn 1387-2877ca
• dc.identifier.uri http://hdl.handle.net/10230/23277
• dc.language.iso engca
• dc.publisher IOS Pressca
• dc.relation.ispartof Journal of Alzheimer's Disease. 2012;30(2):439-59
• dc.rights © IOS Press. All rights reservedca
• dc.rights.accessRights info:eu-repo/semantics/openAccessca
• dc.subject.other Alzheimer, Malaltia d'
• dc.subject.other Farmacologia
• dc.subject.other Genètica
• dc.title CB1 agonist ACEA protects neurons and reduces the cognitive impairment of AβPP/PS1 miceca
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/acceptedVersionca