Alzheimer's amyloid beta-peptide enhances ATP/gap junction-mediated calcium-wave propagation in astrocytes.
Alzheimer's disease (AD) involves the progressive extracellular deposition of amyloid beta-peptide (Abeta), a self-aggregating 40-42 amino acid protein that can damage neurons resulting in their dysfunction and death. Studies of neurons have shown that Abeta perturbs cellularcalcium homeostasis so that calcium responses to agonists that induce calcium influx or release from internal stores are increased. The recent discovery of intercellular calcium waves in astrocytes suggests intriguing roles for astrocytes in the long-range transfer of information in the nervous system. We now report that Abeta alters calcium-wave signaling in cultured rat cortical astrocytes. Exposure of astrocytes to Abeta1-42 resulted in an increase in the amplitude and velocity of evoked calcium waves, and increased the distance the waves traveled. Suramin decreased wave propagation in untreated astrocytes and abrogated the enhancing effect of Abeta on calciumwave amplitude and velocity, indicating a requirement for extracellular ATP in wave propagation. Treatment of astrocytes with an uncoupler of gap junctions did not significantly reduce the amplitude, velocity, or distance of calcium waves in control cultures, but completely abolished the effects of Abeta on each of the three wave parameters. These findings reveal a novel action of Abeta on the propagation of intercellular calcium signals in astrocytes, and also suggests a role for altered astrocyte calcium-signaling in the pathogenesis of AD.
Haughey
Norman J
NJ
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
Mattson
Mark P
MP
D000255:Adenosine Triphosphate / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology*; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D000442:Octanols / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013498:Suramin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D016229:Amyloid beta-Peptides; D015220:Calcium Channels; D000442:Octanols; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D018698:Glutamic Acid; D013498:Suramin; D000255:Adenosine Triphosphate