Research Summary: Effects of Transmitters and Amyloid-Beta Peptide on Calcium Signals in Rat Cortical Astrocytes: Fura-2AM Measurements and Stochastic Model Simulations



To better understand the complex molecular level interactions seen in the
pathogenesis of Alzheimer’s disease, the results of the wet-lab and
clinical studies can be complemented by mathematical models. Astrocytes are
known to become reactive in Alzheimer’s disease and their ionic
equilibrium can be disturbed by interaction of the released and accumulated
transmitters, such as serotonin, and peptides, including
amyloid- peptides
(A). We have here studied the effects of small amounts
of A25–35 fragments on the transmitter-induced
calcium signals in astrocytes by Fura-2AM fluorescence measurements and
running simulations of the detected calcium signals.

Methodology/Principal Findings

Intracellular calcium signals were measured in cultured rat cortical
astrocytes following additions of serotonin and glutamate, or either of
these transmitters together with A25–35.
A25–35 increased the number of astrocytes
responding to glutamate and exceedingly increased the magnitude of the
serotonin-induced calcium signals. In addition to
A25–35-induced effects, the contribution of
intracellular calcium stores to calcium signaling was tested. When using
higher stimulus frequency, the subsequent calcium peaks after the initial
peak were of lower amplitude. This may indicate inadequate filling of the
intracellular calcium stores between the stimuli. In order to reproduce the
experimental findings, a stochastic computational model was introduced. The
model takes into account the major mechanisms known to be involved in
calcium signaling in astrocytes. Model simulations confirm the principal
experimental findings and show the variability typical for experimental


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


Publisher: Public Library of Science

Date Published: 29-March-2011

Author(s): Toivari E., Manninen T., Nahata A., Jalonen T., Linne M.


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