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

TY - JOUR

T1 - Astrocytic C–X–C motif chemokine ligand-1 mediates β-amyloid-induced synaptotoxicity

AU - Perez-Nievas, Beatriz G.

AU - Johnson, Louisa

AU - Beltran-Lobo, Paula

AU - Hughes, Martina M.

AU - Gammallieri, Luciana

AU - Tarsitano, Francesca

AU - Myszczynska, Monika A.

AU - Vazquez-Villasenor, Irina

AU - Jimenez-Sanchez, Maria

AU - Troakes, Claire

AU - Wharton, Stephen B.

AU - Ferraiuolo, Laura

AU - Noble, Wendy

N1 - Funding Information: This work was supported by Alzheimer’s Research UK (King’s College London ARUK Network Centre, ARUK-RF2014-2 to BGP-N, ARUK-EG2013-B1 to WN, ARUK-PhD2018-002 to WN and BGP-N, PG2019A-003 to SBW), the Van Geest Charitable Trust (to BGP-N), a grant from Consejo Nacional de Ciencia y Technologia (CONACyT), Mexico (to IV), a Career Development Award from the Medical Research Council (MR/N022696/1 to MJ-S) and grants from the Thierry Latran Foundation and the Academy of Medical Sciences (Ref: SBF002/1142 to LF). Human tissue samples were provided by the London Neurodegenerative Diseases Brain Bank, which receives funding from the MRC and through the Brains for Dementia Research programme (jointly funded by Alzheimer’s Society and Alzheimer’s Research UK). Publisher Copyright: © 2021, The Author(s).

PY - 2021/12/28

Y1 - 2021/12/28

N2 - 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.

AB - 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.

KW - Alzheimer’s disease

KW - Astrocyte

KW - Beta-amyloid

KW - CXCL1

KW - Synapse

KW - Tau

UR - http://www.scopus.com/inward/record.url?scp=85121832920&partnerID=8YFLogxK

U2 - 10.1186/s12974-021-02371-0

DO - 10.1186/s12974-021-02371-0

M3 - Article

C2 - 34963475

AN - SCOPUS:85121832920

SN - 1742-2094

VL - 18

JO - Journal of neuroinflammation

JF - Journal of neuroinflammation

IS - 1

M1 - 306

ER -