Simvastatin overcomes the resistance to serum withdrawal-induced apoptosis of lymphocytes from Alzheimer’s disease patients

Abstract

Statins may exert beneficial effects on Alzheimer's disease (AD) patients. Based on the antineoplastic and apoptotic effects of statins in a number of cell types, we hypothesized that statins may be able to protect neurons by controlling the regulation of cell cycle and/or apoptosis. A growing body of evidence indicates that neurodegeneration involves the cell-cycle activation in postmitotic neurons. Failure of cell-cycle control is not restricted to neurons in AD patients, but occurs in peripheral cells as well. For these reasons, we studied the role of simvastatin (SIM) on cell survival/death in lymphoblasts from AD patients. We report here that SIM induces apoptosis in AD lymphoblasts deprived of serum. SIM interacts with PI3K/Akt and ERK1/2 signaling pathways thereby decreasing the serum withdrawal-enhanced levels of the CDK inhibitor p21(Cip1) (p21) and restoring the vulnerability of AD cells to trophic factor deprivation.

Downregulation of extracellular signal-regulated kinase 1/2 activity by calmodulin KII modulates p21Cip1 levels and survival of immortalized lymphocytes from Alzheimer’s disease patients

“…1D, AD lymphoblasts displayed higher activity of CaMKII, as monitored by the enhanced autophosphorylation, together with decreased ERK1/2 activity, when compared with control cells. In parallel, levels of p21 increased in agreement with previous reports (Bartolome, et al, 2010). Moreover, as it was the case for changes in other cell cycle-related events reported in AD lymphoblasts (Bartolome, et al, 2009), we did not observe significant differences in p21 content among mild, moderate or severe AD patients (results not shown).…”

“…On the contrary, the ERK1/2 inhibitor PD98059 was able to increase p21 mRNA levels in control cells without affecting the transcription of the gene in AD lymphoblasts. Under these conditions, and in agreement with previous reports (Bartolome, et al, 2010), control cells were found to be resistant to cell death induced by serum deprivation (Fig. 1C).…”

“…Experimental evidence supports the idea that important oncogenic kinases such as PI3K/AKT, IKK and ERK1/2 are involved in regulating FOXO3a nuclear localization and activity through phosphorylation at different sites (Hu, et al, 2004, Plas and Thompson, 2003, Yang, et al, 2008. However, in human lymphoblasts, inhibition of PI3K/Akt has no consequences in the transcription of p21 (this manuscript) or in p21 levels and cell survival (Bartolome, et al, 2010). Our data indicate that inhibiting ERK1/2 activity by PD98059 might prevent phosphorylation of FOXO3a, allowing the nuclear accumulation of FOXO3a, increasing its transcriptional activity and blocking the serum withdrawal-induced death in control lymphoblasts.…”

“…Two cell cycle regulatory proteins, the CDK inhibitors p27 Kip1 and p21 Cip1 , from now on p27 and p21, are ultimately responsible for the enhanced proliferation and increased resistance to cell death, respectively. Whereas downregulation of p27 induces the enhanced proliferative response of immortalized lymphocytes from AD patients (Muñoz, et al, 2008), upregulation of p21 seems to help AD cells to escape from serum deprivation-induced apoptosis (Bartolome, et al, 2010).…”

Altered Calmodulin Degradation and Signaling in Non-Neuronal Cells from Alzheimer’s Disease Patients

“…The activity of other CaM-dependent protein, CAMKII, was also found to increase in lymphoblasts from AD patients. This protein plays an important role in controlling the cellular response to serum-deprivation-induced apoptosis in immortalized lymphocytes [25,26].…”