Astrocytic C-X-C motif chemokine ligand-1 mediates β-amyloid-induced synaptotoxicity

Abstract

Pathological interactions between beta-amyloid (Aβ) and tau drive the synapse loss that underlies neural circuit disruption and cognitive decline in Alzheimer's disease (AD). Reactive astrocytes, displaying altered functions, are also a prominent feature of AD brain. This large and heterogeneous population of cells are increasingly recognised as contributing to early phases of disease. However, the contribution of astrocytes to Aβ-tau interactions in AD is not well understood. Here we stimulated mouse and human astrocytes with concentrations and species of human Aβ that mimic those in human AD brain. Astrocyte conditioned medium was collected and immunodepleted of Aβ before being added to rodent and human neuron cultures. Cytokines, identified in unbiased screens, were also applied to neurons, including following the pre-treatment of neurons with chemokine receptor antagonists. Tau mislocalisation, synaptic markers and dendritic spine numbers were measured in cultured neurons and organotypic brain slice cultures. Conditioned medium from astrocytes stimulated with Aβ induced tau mislocalisation and exaggerated synaptotoxicity that is recapitulated following spiking of neuron culture medium with recombinant C-X-C motif chemokine ligand-1 (CXCL1), a chemokine we show to be upregulated in Alzheimer's disease brain. Antagonism of neuronal C-X-C motof chemokine receptor 2 (CXCR2), prevented tau mislocalisation and synaptotoxicity in response to CXCL1 and Aβ-stimulated astrocyte secretions. Our data indicate that astrocytes exacerbate tau mislocalisation and the synaptotoxic effects of Aβ via interactions of astrovyctic CXCL1 and the neuronal CXCR2 receptor, highlighting this chemokine-receptor pair as a novel target for therapeutic intervention in AD.