The PHA-induced calcium signal in lymphocytes is altered after blockade of K+-channels in Alzheimer's disease

Several lines of evidence indicate that alterations in intracellular calcium homeostasis with sustained elevation of free calcium ions ([Ca2+](i)) might be important in the pathophysiology of Alzheimer's disease (AD). Recent studies with peripheral blood-cells have demonstrated that investigation of regulatory mechanisms in calcium homeostasis might be more promising than determining only resting or stimulated [Ca2+](i) values. With respect to the importance of potassium (K+)-channels in intracellular calcium regulation we have investigated whether a potassium channel dysfunction, already demonstrated for AD fibroblasts (Etcheberrigaray et al., 1993, Proceedings of National Academy of Sciences USA, 90, 8209-8213), could be observed in circulating lymphocytes as well. Thus, we studied the influence of the K+-channel inhibitor tetraethylammonium (TEA) on basal and PHA-stimulated [Ca2+](i) in lymphocytes from AD (n = 20), non-demented depressed patients (n = 15) and age-related healthy controls (n = 23). Preincubation of lymphocytes with 100 mmol/l TEA resulted in a 45.5 +/- 8.8 % inhibition (mean +/- SD) of the PHA induced rise in [Ca2+](i) in healthy controls and 37.3 +/- 11.3 % inhibition in depressed patients. With lymphocytes of AD patients, this effect of TEA was significantly reduced (23.2 +/- 8.8 %; p < .001). If the individual data are considered there was almost no overlap between AD patients and healthy controls, since only three (15 %) AD patients responded to TEA with > 30 % inhibition, but only one of the controls (5 %) responded with < 30 % inhibition. Besides the reduced signal-inhibition by blockade of K+-channels we have observed a delayed response of AD lymphocytes in [Ca2+](i) rise after PHA stimulation, suggesting that functional plasticity of the cells is reduced. Although the significance and molecular basis of this K+-channel dysfunction are not yet determined, the presented data are of great significance because of diagnostic reasons and especially because this model thus offers a possibility to investigate functional cellular alterations in vivo. Copyright (C) 1996 Elsevier Science Ltd.