Tauopathies are a group of neurodegenerative diseases characterized by the progressive accumulation across the brain of hyperphosphorylated aggregates of the microtubule-associated protein tau that vary in isoform composition, structural conformation and localization. Tau aggregates are most commonly deposited within neurons but can show differential association with astrocytes, depending on the disease. Astrocytes, the most abundant neural cells in the brain, play a major role in synapse and neuronal function, and are a key component of the glymphatic system and blood brain barrier. However, their contribution to tauopathy progression is not fully understood. Here we present a brief overview of the association of tau with astrocytes in tauopathies. We discuss findings that support a role for astrocytes in the uptake and spread of pathological tau, and we describe how alterations to astrocyte phenotype in tauopathies may cause functional alterations that impedes their ability to support neurons and/or cause neurotoxicity. The research reviewed here further highlights the importance of considering non-neuronal cells in neurodegeneration and suggests that astrocyte-directed targets that may have utility for therapeutic intervention in tauopathies.

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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.

Aims  The cardiac ryanodine receptor (RyR2), which mediates intracellular Ca2+ release to trigger cardiomyocyte contraction, participates in development of acquired and inherited arrhythmogenic cardiac disease. This study was undertaken to characterize the network of inter- and intra-subunit interactions regulating the activity of the RyR2 homotetramer. Methods and results  We use mutational investigations combined with biochemical assays to identify the peptide sequence bridging the β8 with β9 strand as the primary determinant mediating RyR2 N-terminus self-association. The negatively charged side chains of two aspartate residues (D179 and D180) within the β8–β9 loop are crucial for the N-terminal inter-subunit interaction. We also show that the RyR2 N-terminus domain interacts with the C-terminal channel pore region in a Ca2+-independent manner. The β8–β9 loop is required for efficient RyR2 subunit oligomerization but it is dispensable for N-terminus interaction with C-terminus. Deletion of the β8–β9 sequence produces unstable tetrameric channels with subdued intracellular Ca2+ mobilization implicating a role for this domain in channel opening. The arrhythmia-linked R176Q mutation within the β8–β9 loop decreases N-terminus tetramerization but does not affect RyR2 subunit tetramerization or the N-terminus interaction with C-terminus. RyR2R176Q is a characteristic hypersensitive channel displaying enhanced intracellular Ca2+ mobilization suggesting an additional role for the β8–β9 domain in channel closing. Conclusion  These results suggest that efficient N-terminus inter-subunit communication mediated by the β8–β9 loop may constitute a primary regulatory mechanism for both RyR2 channel activation and suppression.

Pathological interactions between beta-amyloid (Aβ) and tau drive the synapse loss that underlies neural circuit disruption 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-tau interactions in AD is not well understood. Here we stimulated mouse and human astrocytes with concentrations and species of human Aβ that mimic those in human AD brain. Astrocyte conditioned medium was collected and immunodepleted of Aβ before being added to rodent and 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. Conditioned medium from astrocytes stimulated with Aβ induced 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 Alzheimer's disease brain. Antagonism of neuronal C-X-C motof chemokine receptor 2 (CXCR2), prevented tau mislocalisation and synaptotoxicity in response to CXCL1 and Aβ-stimulated astrocyte secretions. Our data indicate that astrocytes exacerbate tau mislocalisation and the synaptotoxic effects of Aβ via interactions of astrovyctic CXCL1 and the neuronal CXCR2 receptor, highlighting this chemokine-receptor pair as a novel target for therapeutic intervention in AD.

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In upcoming issues of EYE, Louisa Johnson, an early childhood studies graduate from University of Chichester, will be sharing her research on the impact of the COVID-19 pandemic on families with babies. Here she introduces her research..