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bioRxiv · 10.1101/2021.09.22.458716

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

Perez-Nievas, B. G.·Johnson, L.·Beltran-Lobo, P.·Hughes, M. M.·Gammallieri, L.·Tarsitano, F.·Myszczynska, M. A.·Vazquez-Villasenor, I.·Jimenez-Sanchez, M.·Troakes, C.·Wharton, S. B.·Ferraiuolo, L.·Noble, W.
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Abstract

BackgroundPathological interactions between {beta}-amyloid (A{beta}) and tau drive the synapse loss that underlies neural circuit disruption and cognitive decline in Alzheimers 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 detrimental A{beta}-tau interactions in AD is not well understood. MethodsMouse and human astrocyte cultures were stimulated with concentrations and species of human A{beta} that mimic those in human AD brain. Astrocyte conditioned medium was collected and immunodepleted of A{beta} before being added to rodent or 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. ResultsConditioned medium from astrocytes stimulated with A{beta} induces 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 Alzheimers disease brain. Antagonism of neuronal C-X-C motif chemokine receptor 2 (CXCR2) prevented tau mislocalisation and synaptotoxicity in response to CXCL1 and A{beta}-stimulated astrocyte secretions. ConclusionsOur data indicate that astrocytes exacerbate tau mislocalisation and the synaptotoxic effects of A{beta} via interactions of astrocytic CXCL1 and neuronal CXCR2 receptors, highlighting this chemokine-receptor pair as a novel target for therapeutic intervention in AD.

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Perez-Nievas, B. G., Johnson, L., Beltran-Lobo, P., Hughes, M. M., Gammallieri, L., Tarsitano, F., Myszczynska, M. A., Vazquez-Villasenor, I., Jimenez-Sanchez, M., Troakes, C., Wharton, S. B., Ferraiuolo, L., Noble, W.. 2021-09-22. Astrocytic C-X-C motif chemokine ligand-1 mediates β-amyloid-induced tau mislocalization and synaptotoxicity. https://doi.org/10.1101/2021.09.22.458716

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