Enhanced proliferation of lymphoblasts from patients with Alzheimer dementia associated with calmodulin-dependent activation of the Na+/H+ exchanger

We have recently reported that lymphoblasts from late onset Alzheimer's dis ease (AD) patients show distinct intracellular pH homeostatic features than those obtained from age-matched healthy donors. Here we report that anothe r distinct feature of AD lymphoblasts is their increased rate of proliferat ion in serum containing medium, suggesting a different responsiveness of AD cells to serum activators. The increased proliferation of AD cells was acc ompanied by intracellular alkalinization and was prevented by blockers of t he plasma membrane Na+/H+ antiporter (NHE), indicating that the exchanger h ad to be activated to elicit the cellular responses. The activity of this e xchanger can be controlled through several signaling pathways, but only the inhibition of calmodulin activity impeded the serum-induced intracellular alkalinization and enhanced proliferation of AD cells. In contrast, the inh ibition of calmodulin did not alter the rate of proliferation of normal cel ls. Thus, it seems plausible to conclude that the enhanced proliferation of AD cells is the result of a surface receptor-mediated activation of the Ca 2+-caamoduuln signaling pathway. Our observations add further support in fa vor that AD may be considered a systemic disease which underlying etiopatho genic mechanism may be an altered responsiveness to cell activating agents. Thus, the use of lymphoblastoid cells from AD patients may be a useful mod el to investigate cell biochemical aspects of this disease. (C) 2001 Academ ic Press.