Picomolar Amyloid-β Peptides Enhance Spontaneous Astrocyte Calcium Transients

Amyloid-beta (A beta) peptides are constitutively produced in the brain throughout life via mechanisms that can be regulated by synaptic activity. Although A beta 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 A beta 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 A beta signaling. Using calcium imaging of primary astrocyte cultures, we observed that picomolar amounts of A beta peptides can enhance spontaneous intracellular calcium transient signaling. After application of 200pM A beta 42 peptides, the frequency and amplitude averages of spontaneous cytosolic calcium transients were significantly increased. These effects were dependent on alpha 7 nicotinic acetylcholine receptors (alpha 7-nAChRs), as the enhancement effects were blocked by a pharmacological alpha 7-nAChR inhibitor and in astrocytes from an alpha 7 deficient mouse strain. We additionally examined evoked intercellular calcium wave signaling but did not detect significant picomolar A beta-induced alterations in propagation parameters. Overall, these results indicate that at a physiologicallyrelevant low picomolar concentration, A beta peptides can enhance spontaneous astrocyte calcium transient signaling via alpha 7-nAChRs. Since astrocyte-mediated gliotransmission has been previously found to have neuromodulatory roles, A beta 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.