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CB1 agonist ACEA protects neurons and reduces the cognitive impairment of AβPP/PS1 mice
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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.
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ASO PÉREZ, Ester, PALOMER, Ernest, JUVÉS, Salvador, MALDONADO, Rafael, MUÑOZ, Francisco j., FERRER, Isidro (ferrer abizanda). CB1 agonist ACEA protects neurons and reduces the cognitive impairment of AβPP/PS1 mice. _Journal of Alzheimer's Disease_. 2012. Vol. 30, núm. 2, pàgs. 439-459. [consulta: 21 de gener de 2026]. ISSN: 1387-2877. [Disponible a: https://hdl.handle.net/2445/96453]