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

Beatriz Gomez Perez-Nievas, Louisa Johnson, Paula Beltran Lobo, Martina Hughes, Luciana Gammallieri, Fransesca Tarsitano, Monika Myszczynska, Irina Vazquez-Villasenor2, Maria Jimenez Sanchez, Claire Troakes, Stephen Wharton, Laura Ferraiuolo, Wendy Noble

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Abstract

Background
Pathological interactions between β-amyloid (Aβ) and tau drive synapse loss 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-induced synaptotoxicity in AD is not well understood.

Methods
We stimulated mouse and human astrocytes with conditioned medium containing concentrations and species of human Aβ that mimic those in human AD brain. Medium from stimulated astrocytes was collected and immunodepleted of Aβ before being added to naïve rodent or human neuron cultures. A cytokine, identified in unbiased screens of stimulated astrocyte media and in postmortem human AD brain lysates was also applied to neurons, including those pre-treated with a chemokine receptor antagonist. Tau mislocalisation, synaptic markers and dendritic spine numbers were measured in cultured neurons and organotypic brain slice cultures.

Results
We found that conditioned medium from stimulated astrocytes induces exaggerated synaptotoxicity that is recapitulated following spiking of neuron culture medium with recombinant C–X–C motif chemokine ligand-1 (CXCL1), a chemokine upregulated in AD brain. Antagonism of neuronal C–X–C motif chemokine receptor 2 (CXCR2) prevented synaptotoxicity in response to CXCL1 and Aβ-stimulated astrocyte secretions.

Conclusions
Our data indicate that astrocytes exacerbate the synaptotoxic effects of Aβ via interactions of astrocytic CXCL1 and neuronal CXCR2 receptors, highlighting this chemokine–receptor pair as a novel target for therapeutic intervention in AD.
Original languageEnglish
Article number306
Number of pages17
JournalJournal of neuroinflammation
DOIs
Publication statusPublished - 28 Dec 2021

Keywords

  • Alzheimer's disease
  • astrocyte
  • tau
  • synapse
  • CXCL1
  • neurodegeneration
  • cytokine
  • neuroinflammation

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