Astrocytes respond to a neurotoxic A\u03b2 fragment with state-dependent Ca2+ alteration and multiphasic transmitter release

Cuong Pham,Karine Hérault,Dongdong Li,Steeve Maldera,Vincent Vialou,Martin Oheim,Bruno Cauli

doi:10.1186/s40478-021-01146-1

Abstract

Excessive amounts of amyloid β (Aβ) 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 Aβ exposure. Yet the mechanistic steps underlying astrocytic responses to Aβ peptide remain to be elucidated. Here by fluorescence imaging of signaling pathways, we dissected astrocytic responses to Aβ25–35 peptide, a neurotoxic Aβ fragment present in AD patients. In native health astrocytes, Aβ25–35 evoked Ca2+ elevations via purinergic receptors, being also dependent on the opening of connexin (CX) hemichannels. Aβ25–35, however, induced a Ca2+ diminution in Aβ-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 Aβ exposure, with the former mediated by CX hemichannel and the latter by both anion channels and lysosome exocytosis. Our results suggest that Aβ 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.

Highlights

Toxic amyloid β (Aβ) peptides are implicated in the development of cognitive deficits of Alzheimer’s disease (AD) [10]
Astrocytic Ca2+ elevation induced by neurotoxic Aβ25–35 To study the acute response of astrocytes to Aβ, we used Total internal reflection fluorescence (TIRF) microscopy (TIRFM) to image near-membrane Ca2+ transients in primary astrocytes cultured from mouse cortex
In this study, we examined the sub-cellular mechanisms underlying the astrocytic response to the neurotoxic amyloid beta fragment

Summary

Introduction

Toxic Aβ peptides are implicated in the development of cognitive deficits of AD [10]. Information processing is sustained by dynamic interactions between neurons and glial cells [13]. Emerging evidence suggests that Aβ dysregulates neuron-glia communication thereby impairing synaptic transmission [33]. Astrocytes are the major glial cell-type in the mammalian brain [34]. Albeit electrically non-excitable, their activity is encoded by intracellular C a2+ signaling [43], which in turn modulates neuron activity, via for instance regulating ambient transmitter and ion recycling [19, 91], the delivery of energy fuels [76], the peri-synaptic structural remodeling [69] as well as the release of transmitter substances [5]. Astrocyte C a2+ activity has been shown to be upregulated by Aβ peptides [2, 11, 85], and near amyloid plaques in AD mouse models [17, 47]. Inhibiting the C a2+-dependent protein phosphatase calcineurin in astrocytes ameliorates

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Conclusion