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

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.

Proteomics of the astrocyte secretome reveals changes in their response to soluble oligomeric Aß

“…To investigate changes in the astrocyte secretome in response to soluble Aß oligomers similar to those found in human disease brain, we exposed primary mouse astrocytes to conditioned media of neurons derived from Tg2576 mouse embryos that express a human APP transgene harbouring the double Swedish mutation K670N, M671L (APPSwe, Hsiao et al 1996) or from their wild type littermates (WT) (Figure 1A). The presence of low molecular weight Aß oligomers in Tg2576 media has been widely characterized (Wu et al 2010;DaRocha-Souto et al 2012;Perez-Nievas et al 2021), with Aß42:Aß40 ratios of 1:10 as in human AD brain, and concentrations ranging between 2 and 8 nM, similar to what it has been reported in human CSF (Snider et al 2009). Conditioned media was diluted to treat primary astrocytes with 2 nM and 0.2 nM concentration of Aß40 and Aß42 oligomers, respectively.…”

“…Astrocytes react to Aß plaques in AD, however, the specific functional changes that this reactivity causes and the implications in the onset and progression of AD remains uncertain. Exposure to extracellular Aß induces an astrocytic response in culture, as evidenced by an increase in astrocyte-mediated neurotoxicity through release of N-SMase (Jana and Pahan 2010) and soluble inflammatory factors (Garwood et al 2011), or increased synaptotoxicity mediated by the secretion of factors such as glutamate (Talantova et al 2013), complement C3 (Lian et al 2015; 2016), or CXCL1 (Perez-Nievas et al 2021). Additionally, Aß exposure may interfere with astrocytic protective functions as it results in decrease secretion of synaptogenic factors such as TSP-1 (Rama Rao et al 2013) or TGF-ß1 (Diniz et al 2017) and impairs phagocytosis and degradation of dystrophic neurites (Sanchez-Mico 2021).…”

Astrocytes in Neurodegeneration: Inspiration From Genetics

“…Astrocytes have long-term effects on synapses by releasing growth factors. However, toxicity to synapses was produced in reactive astrocytes via several pathways, including ATP deficiency, ion metabolisms dysfunction, and damaged ion channels, all of which degrade the synaptic integrity (Cervetto et al, 2021;Huiliang et al, 2021;Perez-Nievas et al, 2021).…”

Hub Genes, Diagnostic Model, and Predicted Drugs Related to Iron Metabolism in Alzheimer's Disease

“…In addition, a promising lead compound promoting IL-10 activity was provided, confirming that promoting IL-10 expression may be useful to treat AD and stroke (Sun P. et al, 2020 ). The interaction between astrocytic CXCL1 and neuronal CXCR2 receptors exacerbates the synaptotoxic effects of Aβ and is expected to serve as a novel target for the treatment of AD (Perez-Nievas et al, 2021 ). CX3CL1 was found to be decreased in the cerebrospinal fluid of patients with AD (Perea et al, 2018 ), which is consistent with our findings.…”