RESUMO
It has been proposed that neuroinflammation, among other factors, may trigger an aberrant neuronal cell cycle re-entry leading to neuronal death. Cell cycle disturbances are also detectable in peripheral cells from Alzheimer's disease (AD) patients. We previously reported that the anti-inflammatory 15- deoxy-Delta(12,14)-prostaglandin J (2) (15d-PGJ (2)) increased the cellular content of the cyclin-dependent kinase inhibitor p27, in lymphoblasts from AD patients. This work aimed at elucidating the mechanisms of 15d-PGJ (2)-induced p27 accumulation. Phosphorylation, half-life, and the nucleo-cytoplasmic traffic of p27 protein were altered by 15d-PGJ2 by mechanisms dependent on PI3K/Akt activity. 15d-PGJ (2) prevents the calmodulin-dependent Akt overactivation in AD lymphoblasts by blocking its binding to the 85-kDa regulatory subunit of PI3K. These effects of 15d-PGJ (2) were not mimicked by 9,10-dihydro-15-deoxy-Delta(12,14)- prostaglandin J (2), suggesting that 15d-PGJ (2) acts independently of peroxisome proliferator-activated receptor gamma activation and that the alpha,beta-unsaturated carbonyl group in the cyclopentenone ring of 15d-PGJ (2) is a requisite for the observed effects.