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.
Bondy
B
B
Psychiatrische Klinik der Universität München, Germany.
Hofmann
M
M
Müller-Spahn
F
F
Witzko
M
M
Hock
C
C
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000276:immunology / Q000503:physiopathology*; D002118:Calcium / Q000097:blood / Q000502:physiology*; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D010835:Phytohemagglutinins / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000494:pharmacology
D010835:Phytohemagglutinins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D013757:Tetraethylammonium Compounds; D019789:Tetraethylammonium; D002118:Calcium