Effects of transmitters and amyloid-beta peptide on calcium signals in rat cortical astrocytes: Fura-2AM measurements and stochastic model simulations

Background

To better understand the complex molecular level interactions seen in thepathogenesis of Alzheimer''s disease, the results of the wet-lab andclinical studies can be complemented by mathematical models. Astrocytes areknown to become reactive in Alzheimer''s disease and their ionicequilibrium can be disturbed by interaction of the released and accumulatedtransmitters, such as serotonin, and peptides, includingamyloid- peptides(A). We have here studied the effects of small amountsof A25–35 fragments on the transmitter-inducedcalcium signals in astrocytes by Fura-2AM fluorescence measurements andrunning simulations of the detected calcium signals.

Methodology/Principal Findings

Intracellular calcium signals were measured in cultured rat corticalastrocytes following additions of serotonin and glutamate, or either ofthese transmitters together with A25–35.A25–35 increased the number of astrocytesresponding to glutamate and exceedingly increased the magnitude of theserotonin-induced calcium signals. In addition toA25–35-induced effects, the contribution ofintracellular calcium stores to calcium signaling was tested. When usinghigher stimulus frequency, the subsequent calcium peaks after the initialpeak were of lower amplitude. This may indicate inadequate filling of theintracellular calcium stores between the stimuli. In order to reproduce theexperimental findings, a stochastic computational model was introduced. Themodel takes into account the major mechanisms known to be involved incalcium signaling in astrocytes. Model simulations confirm the principalexperimental findings and show the variability typical for experimentalmeasurements.

Conclusions/Significance

Nanomolar A25–35 alone does not cause persistent change inthe basal level of calcium in astrocytes. However, even small amounts ofA25–35, together with transmitters, can havesubstantial synergistic effects on intracellular calcium signals.Computational modeling further helps in understanding the mechanismsassociated with intracellular calcium oscillations. Modeling the mechanismsis important, as astrocytes have an essential role in regulating theneuronal microenvironment of the central nervous system.