On the mechanism of inhibition of p27 degradation by 15-deoxy-Δ12,14-prostaglandin J 2 in lymphoblasts of Alzheimer’s disease patients

Abstract

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.

Cell cycle and Alzheimer's disease: studies in non-neuronal cells

“…As reported for other cell types (Pérez-García et al 2004), we were able to observe that CaM binds to the p85α subunit of PI3K (Muñoz et al 2008b). Therefore, CaM could contribute to PI3K overactivation in AD cells through this mechanism, as association of CaM with the SH2 domain in p85 leads to PI3K activation (Pérez-García et al 2004).…”

“…CaM antagonists had no effect in control cells, suggesting a threshold for CaM activation as the survival signal (de las , Bartolomé et al 2007, Muñoz et al 2008a. In fact, higher CaM content was found in lymphoblasts from AD patients (Muñoz et al 2008b).…”

“…Interestingly, the enhanced proliferative activity and changes in cell cycle regulatory proteins, can be modulated pharmacologically by treating AD cells with the anti-inflammatory cyclopentenone 15-deoxy-prostaglanding J 2 or simvastatin , 2008b, Sala et al 2008. Therefore these observations provide a plausible explanation for the reported apparent benefits of these drugs preventing or delaying the clinical features of AD (Stewart et al 1997, Wolozin et al 2000.…”

Activation of the Cannabinoid Type 2 Receptor by a Novel Indazole Derivative Normalizes the Survival Pattern of Lymphoblasts from Patients with Late-Onset Alzheimer’s Disease

“…The re-entry of quiescent neurons into the cell cycle may result in a mitotic failure and cell death [5,6,31]. Moreover, lymphoblastoid cell lines from AD patients have been previously used as a platform to test the therapeutic potential of certain drugs [32][33][34]. Here we report the ability of one in-house designed CB2 agonist with additional cholinergic activity in normalizing the aberrant proliferation and signaling of lymphoblasts from AD patients.…”

Anti-Inflammatory Prostanoids: Focus on the Interactions between Electrophile Signaling and Resolution of Inflammation

“…The cellular mechanisms involved in the antiproliferative effects of cyPG may be multiple and dependent on the biological system under study. cyPG have been shown to induce apoptosis or cell cycle arrest in association with modulation of cell cycle regulatory proteins, such as cyclins D1 and B1 [32,33], cyclin Aand cyclin E-dependent kinases [34], or cyclin-dependent kinase inhibitors [35]. Induction of apoptosis by cyPG or cyPG analogs may also result from mitochondria and/or NADPH oxidase-derived oxidative stress [36].…”