There is growing evidence that the amyloid beta-peptide (beta 1-40) is involved in the aetiology of Alzheimer's disease also implicating an altered calcium homeostasis of affected cells. Beta 1-40 has been proposed to form calcium channels in synthetic bilayer membranes [1]. We wanted to investigate in the present study whether beta 1-40 (or fragments thereof) could act as ionophores in a biological membrane like the one in human erythrocytes. Incubation of the cells for 2 h and 4 h at 37 degrees C together with 6 mumol L-1 of beta 1-40 or of fragments beta 1-28 and beta 25-35, resulted in a significantly decreased energy charge qualitatively similar to the one obtained by a known calcium ionophore (A 23187, 0.05 mumol L-1). Moreover, beta 1-40 and its two fragments induced a significant alteration of 45Ca permeability in human red blood cells of the same type as the one achieved by the calcium ionophore. The ionophoric action of beta 1-40 and its two fragments may lead to an increase of the intracellular calcium ion concentration, in turn resulting in enhanced Ca(2+)-ATPase activity and a decrease in energy charge. This may be valid also for neuronal plasma membranes and could, therefore, be a possible aetiological mechanism in Alzheimer's disease.

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Washed human erythrocytes were basically incubated in phosphate-buffered saline at 37 degrees C with different concentrations (1-5 mumol l-1) of the divalent cationophore A23187. This ionophore induced a decrease by about 75% of ATP content and energy charge (EC) and a concomitant increase in ADP and AMP contents in a dose-dependent fashion such that an inverse ATP/ADP relationship developed. EGTA at 1 mumol l-1 annihilated the effect of A23187 on energy status. When glucose was added to the basic incubation medium A23187 inclusion resulted in an elevated lactate production concomitantly with a partial restoration of EC. Introduction of Mg2+ to basic incubation medium containing glucose and the ionophore resulted in a sharp increase in lactate production with an energy state that was maintained at a control level. It is concluded that the low EC of erythrocytes obtained by this ionophore is the result of runaway ATPases dissociated from glycolysis. Since human erythrocytes are devoid of organelles other than the plasma membrane it is concluded that the ionophoric effect is exerted in the plasma membrane.

Abstract. Waldenstro Èm A, Engstro Èm I, Ronquist G