B. Bondy et al., THE PHA-INDUCED CALCIUM SIGNAL IN LYMPHOCYTES IS ALTERED AFTER BLOCKADE OF K-CHANNELS IN ALZHEIMERS-DISEASE(), Journal of Psychiatric Research, 30(3), 1996, pp. 217-227
Several lines of evidence indicate that alterations in intracellular c
alcium homeostasis with sustained elevation of free calcium ions ([Ca2
+](i)) might be important in the pathophysiology of Alzheimer's diseas
e (AD). Recent studies with peripheral blood-cells have demonstrated t
hat investigation of regulatory mechanisms in calcium homeostasis migh
t 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 pot
assium channel dysfunction, already demonstrated for AD fibroblasts (E
tcheberrigaray et al., 1993, Proceedings of National Academy of Scienc
es USA, 90, 8209-8213), could be observed in circulating lymphocytes a
s well. Thus, we studied the influence of the K+-channel inhibitor tet
raethylammonium (TEA) on basal and PHA-stimulated [Ca2+](i) in lymphoc
ytes from AD (n = 20), non-demented depressed patients (n = 15) and ag
e-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 patien
ts, this effect of TEA was significantly reduced (23.2 +/- 8.8 %; p <
.001). If the individual data are considered there was almost no overl
ap between AD patients and healthy controls, since only three (15 %) A
D patients responded to TEA with > 30 % inhibition, but only one of th
e controls (5 %) responded with < 30 % inhibition. Besides the reduced
signal-inhibition by blockade of K+-channels we have observed a delay
ed response of AD lymphocytes in [Ca2+](i) rise after PHA stimulation,
suggesting that functional plasticity of the cells is reduced. Althou
gh 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 o
ffers a possibility to investigate functional cellular alterations in
vivo. Copyright (C) 1996 Elsevier Science Ltd.