Altered transcriptional regulators in response to serum in immortalized lymphocytes from Alzheimer's disease patients

Cell cycle disturbances may precede neuronal death in Alzheimer's disease (AD). We described alterations, in lymphocytes from AD patients. on the activity of two transcription factors, E2F and NF-kappaB, involved in cell proliferation and survival regulation, demonstrating that cell cycle dysfunction also occurs in peripheral cells. The analysis of E2F-DNA binding activity revealed lower signal intensity of protein-DNA complexes in AD cells, which correlated with increased phosphorylation of retinoblastoma (pRb) related proteins and enhanced proliferation. The calmodulin (CaM) antagonist calmidazolium (CMZ) abrogated the increased activity of AD cells by partially dephosphorylating pRb and p130. The NF-kappaB-DNA binding activity increased as cell progress through the cell cycle. The reduced NF-kappaB activation observed in AD cells appears not to be related to the increased phosphorylation of the pRb family proteins nor with the enhanced proliferative activity of AD cells, but seems to protect them from death induced by the loss of trophic support. Ca2+/CaM antagonists rescue NF-kappaB-DNA binding activity and sensitize AD cells to serum withdrawal. These observations suggest that disruption of Ca2+/CaM signaling pathway could be linked mechanistically to its pro cell survival actions, promoting enhanced proliferation or decreased cell death depending on the presence of growth-stimulatory signals. (C) 2004 Elsevier Inc. All rights reserved.