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.

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Astrocytes are key homeostatic and defensive cells of the central nervous system (CNS). They undertake numerous functions during development and in adulthood to support and protect the brain through finely regulated communication with other cellular elements of the nervous tissue. In Alzheimer’s disease (AD), astrocytes undergo heterogeneous morphological, molecular and functional alterations represented by reactive remodelling, asthenia and loss of function. Reactive astrocytes closely associate with amyloid β (Aβ) plaques and neurofibrillary tangles in advanced AD. The specific contribution of astrocytes to AD could potentially evolve along the disease process and includes alterations in their signalling, interactions with pathological protein aggregates, metabolic and synaptic impairments. In this review, we focus on the purinergic receptor, P2X7R, and discuss the evidence that P2X7R activation contributes to altered astrocyte functions in AD. Expression of P2X7R is increased in AD brain relative to non-demented controls, and animal studies have shown that P2X7R antagonism improves cognitive and synaptic impairments in models of amyloidosis and tauopathy. While P2X7R activation can induce inflammatory signalling pathways, particularly in microglia, we focus here specifically on the contributions of astrocytic P2X7R to synaptic changes and protein aggregate clearance in AD, highlighting cell-specific roles of this purinoceptor activation that could be targeted to slow disease progression.

Editorial on the Research Topic Autophagy in the central nervous system: Focus on neurons,glia and neuron-glia interactions Autophagy is a fundamental catabolic recycling process of the cell and plays an essential role in brain physiology and pathology. We can differentiate three major autophagy types that all degrade there cargo via the endo-lysosomal system; chaperone-mediated autophagy (CMA), microautophagy, and macroautophagy. CMA and microautophagy use cytosolic chaperone proteins to transport proteins directly to lysosomes or endosomes respectively. CMA requires the LAMP2A receptor on lysosomes for substrate binding, while microautophagy transfers the cargo by invagination of lysosomal and endosomal membranes. In contrast, macroautophagy (here after called autophagy) consists in the formation of an autophagic membrane that engulfs cytoplasmic material that than fuses with the lysosome to degrade the content.In this Research Topic, we bring together, a collection of articles that highlight the role of autophagy in the brain with particular view on neurons, neuroglia and synaptic compartments, dysregulation of autophagy in neurodegeneration, methods to detect, analyze and quantify autophagy as well as points of therapeutic opportunities in neurodegenerative disease.In neurons, autophagy presents cell specific adaptations. Neurons are highly polarized post-mitotic cells that are particularly sensitive to oxidative stress and the accumulation of dysfunctional and toxic proteins. Moreover, presynaptic compartments can lay sometimes fare away from the soma, have limited local translation mechanisms and these compartments host the areas where synaptic vesicles fuse with the plasma membrane to release neurotransmitter for communication with post synaptic site. The work from Decet and Verstreken summaries our current understanding of

Huntington's disease (HD) is a progressive neurodegenerative condition caused by the abnormal expansion of a polyglutamine tract in the N‐terminus of the huntingtin protein. Over the last 20 years, HD pathogenesis has been explained by the generation of N‐terminal fragments containing the polyglutamine stretch. A new study from Frederic Saudou's group now investigates the function of the C‐terminal fragments generated upon cleavage and shows that these products may also contribute to cellular toxicity in HD (El‐Daher et al, ).