Picomolar amyloid-β peptides enhance spontaneous astrocyte calcium transients.
Amyloid-β (Aβ) peptides are constitutively produced in the brain throughout life via mechanisms that can be regulated by synaptic activity. Although Aβ has been extensively studied as the pathological plaque-forming protein species in Alzheimer's disease (AD), little is known about the normal physiological function(s) and signaling pathway(s). We previously discovered that physiologically-relevant, low picomolar amounts of Aβ can enhance synaptic plasticity and hippocampal-dependent cognition in mice. In this study, we demonstrated that astrocytes are cellular candidates for participating in this type of Aβ signaling. Using calcium imaging of primary astrocyte cultures, we observed that picomolar amounts of Aβ peptides can enhance spontaneous intracellular calcium transient signaling. After application of 200 pM Aβ42 peptides, the frequency and amplitude averages of spontaneous cytosolic calcium transients were significantly increased. These effects were dependent on α7 nicotinic acetylcholine receptors (α7-nAChRs), as the enhancement effects were blocked by a pharmacological α7-nAChR inhibitor and in astrocytes from an α7 deficient mouse strain. We additionally examined evoked intercellular calcium wave signaling but did not detect significant picomolar Aβ-induced alterations in propagation parameters. Overall, these results indicate that at a physiologically-relevant low picomolar concentration, Aβ peptides can enhance spontaneous astrocyte calcium transient signaling via α7-nAChRs. Since astrocyte-mediated gliotransmission has been previously found to have neuromodulatory roles, Aβ peptides may have a normal physiological function in regulating neuron-glia signaling. Dysfunction of this signaling process may underlie glia-based aspects of AD pathogenesis.
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA Department of Pathology and Cell Biology, Columbia University, New York, NY, USA Center for Neurobiology and Behavior, Columbia University, New York, NY, USA.
Linda
L
Lee
Pallav
P
Kosuri
Ottavio
O
Arancio
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects*; D002038:Bungarotoxins / Q000493:pharmacokinetics; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000494:pharmacology; D016548:Prosencephalon / Q000166:cytology; D011485:Protein Binding / Q000187:drug effects; D013997:Time Factors; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000172:deficiency / Q000378:metabolism
D016229:Amyloid beta-Peptides; D002038:Bungarotoxins; D005904:Glial Fibrillary Acidic Protein; D010446:Peptide Fragments; D064569:alpha7 Nicotinic Acetylcholine Receptor; C075222:amyloid beta-protein (1-42); D002118:Calcium
amyloid-β; astrocyte; calcium imaging; glia; gliotransmission; α7 nicotinic acetylcholine receptor