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Article type: Research Article
Authors: Aso, Estera; * | Palomer, Ernestb | Juvés, Salvadora | Maldonado, Rafaelc | Muñoz, Francisco J.b | Ferrer, Isidroa; d
Affiliations: [a] Institut de Neuropatologia, Servei d'Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain | [b] Laboratori de Fisiologia Molecular i Canalopaties, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain | [c] Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain | [d] CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Barcelona, Spain
Correspondence: [*] Correspondence to: Ester Aso, Institut de Neuropatologia, Servei d'Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, C/Feixa Llarga s/n, 08907 L'Hospitalet de Llobregat, Barcelona, Spain. Tel.: +34 93 2607452; Fax: +34 93 2607503; E-mail: [email protected].
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.
Keywords: Alzheimer's disease, astrogliosis, cannabinoid receptor, CB1 cognition, GSK3β, neuroprotection, transgenic mice
DOI: 10.3233/JAD-2012-111862
Journal: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 439-459, 2012
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