Ca2+/calmodulin-dependent modulation of cell cycle elements pRb and p27kip1 involved in the enhanced proliferation of lymphoblasts from patients with Alzheimer dementia

HMG-CoA Reductase Inhibitor Simvastatin Inhibits Cell Cycle Progression at the G1/S Checkpoint in Immortalized Lymphocytes from Alzheimer's Disease Patients Independently of Cholesterol-Lowering Effects

“…Figure 1 shows a time course analysis of the effect of increasing doses of simvastatin on rates of proliferation, upon serum stimulation, of lymphoblasts from control and AD patients. In agreement with previous reports from this laboratory (de las Cuevas et al, 2003;Muñ oz et al, 2005Muñ oz et al, , 2007, the proliferative activity of AD lymphoblasts was significantly higher than that of control cells. Treatment of cells with simvastatin resulted in a significant inhibition of cell growth of both control and AD lymphoblasts in a dosedependent manner.…”

“…Data in Fig. 5 confirm and extend our previous finding (de las Cuevas et al, 2003), showing that both levels and phosphorylation of pRb were increased in AD lymphoblasts (Fig. 5).…”

“…pRb hyperphosphorylation releases E2F transcription factors, thus contributing to the expression of several growth and cell cycle regulatory genes with functional E2F binding sites in their promoters (Stevaux and Dyson, 2002). In agreement with previous reports (de las Cuevas et al, 2003;Muñ oz et al, 2005Muñ oz et al, , 2007 lymphoblasts from AD patients showed a higher degree of phosphorylation of pRb. The addition of SIM had no effect on the phosphorylation status of pRb in control cells, but it significantly reduced the levels of the hyperphosphorylated form of pRb in AD lymphoblasts.…”

“…Previous work from this laboratory demonstrated that the serum-mediated enhancement of AD cell proliferation is the consequence of altered G 1 /S transition (de las Cuevas et al, 2003;Muñ oz et al, 2005). It was shown that serum induced an increase in the expression levels and phosphorylation status of the pRb family proteins in AD lymphoblasts.…”

“…To this aim, we have investigated the effects of simvastatin, a lipophilic statin, on the distinct features of control of cell proliferation in lymphoblasts derived from late-onset AD patients. Previous work from this and other laboratories has demonstrated that cell cycle regulatory deficit is not restricted to neurons in AD; it is also observed in peripheral cells such as lymphocytes or fibroblasts (Tatebayashi et al, 1995;Nagy et al, 2002;de las Cuevas et al, 2003), thus providing a useful tool to study the involvement of cell cyclerelated events in the pathogenesis of AD. A number of studies have found AD-specific changes in molecules and signaling pathways in peripheral lymphocytes that mirror changes in the brain (Eckert et al, 1998;Nagy et al, 2002;.…”