Astrocytes respond to a neurotoxic Aβ fragment with state-dependent Ca2+ alteration and multiphasic transmitter release

Excessive amounts of amyloid beta (A beta) peptide have been suggested to dysregulate synaptic transmission in Alzheimer's disease (AD). As a major type of glial cell in the mammalian brain, astrocytes regulate neuronal function and undergo activity alterations upon A beta exposure. Yet the mechanistic steps underlying astrocytic responses to A beta peptide remain to be elucidated. Here by fluorescence imaging of signaling pathways, we dissected astrocytic responses to A beta 25-35 peptide, a neurotoxic A beta fragment present in AD patients. In native health astrocytes, A beta 25-35 evoked Ca2+ elevations via purinergic receptors, being also dependent on the opening of connexin (CX) hemichannels. A beta 25-35, however, induced a Ca2+ diminution in A beta-preconditioned astrocytes as a result of the potentiation of the plasma membrane Ca2+ ATPase (PMCA). The PMCA and CX protein expression was observed with immunostaining in the brain tissue of hAPPJ20 AD mouse model. We also observed both Ca2+-independent and Ca2+-dependent glutamate release upon astrocytic A beta exposure, with the former mediated by CX hemichannel and the latter by both anion channels and lysosome exocytosis. Our results suggest that A beta peptide causes state-dependent responses in astrocytes, in association with a multiphasic release of signaling molecules. This study therefore helps to understand astrocyte engagement in AD-related amyloidopathy.

Automated summary

This study investigated astrocytic responses to the neurotoxic A beta fragment present in Alzheimer's disease patients through fluorescence imaging of signaling pathways. The results showed that A beta 25-35 induced different Ca2+ responses in astrocytes in different states, accompanied by a multiphasic release of signaling molecules.