CB1 Agonist ACEA Protects Neurons and Reduces the Cognitive Impairment of AβPP/PS1 Mice

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 A beta PP(swe)/PS1(1dE9) transgenic mice from 6 months of age onwards. ACEA has no effect on amyloid-beta (A beta) production, aggregation, or clearance. However, ACEA reduces the cytotoxic effect of A beta(42) oligomers in primary cultures of cortical neurons, and reverses A beta-induced dephosphorylation of glycogen synthase kinase-3 beta (GSK3 beta) in vitro and in vivo. Reduced activity of GSK3 beta in ACEA-treated mice is further supported by the reduced amount of phospho-tau (Thr181) in neuritic processes around A beta plaques. In addition, ACEA-treated mice show decreased astroglial response in the vicinity of A beta plaques and decreased expression of the pro-inflammatory cytokine interferon-gamma 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 GSK3 beta inhibition, and glial levels, resulting in a reduction of reactive astrocytes and lower expression of interferon-gamma. As a consequence, targeting the CB1 receptor could offer a versatile approach for the treatment of Alzheimer's disease.