Astrocyte Proximity Protects Synapses From Human Amyloid-Beta Induced Degeneration in a Mouse Ex Vivo Model of Early Alzheimer's Disease

Synapse loss is the strongest pathological correlate of cognitive decline in Alzheimer's disease (AD) and is most pronounced around amyloid plaque pathology in the brain. Although mechanisms remain incompletely understood, hyperactivity downstream of soluble amyloid beta (Aβ) is strongly implicated in synapse degeneration. Engulfment of synapses by reactive astrocytes was observed in end-stage disease tissue, particularly around plaques. Due to astrocytes' role in synaptic modulation, we hypothesised that astrocytes could modulate synapse degeneration downstream of soluble Aβ earlier in disease pathogenesis. To test this, we challenged organotypic mouse brain slices with human AD brain homogenates containing Aβ. Changes in synaptic activity were detected 2 h after Aβ challenge, and spine loss was seen after 24 h. We observe that Aβ-containing homogenate induces a significant loss of spines compared with controls. Aβ-containing homogenate also causes a significant increase in the frequency of synaptic calcium events, particularly in synapses lost at 24 h. Dendritic spines associated with astrocytic processes were significantly more likely to survive at 24 h after Aβ challenge and had reduced levels of externalised phosphatidyl serine despite no effect of astrocyte proximity on synaptic activity. Inhibiting astrocytic glutamate transporters prevented the protective effects of astrocytes on synapses, indicating that astrocytes are protective of synapses at least in part through removing excess glutamate from the synaptic microenvironment. Our findings suggest that an organotypic mouse brain slice model challenged with disease tissue homogenates effectively recapitulates key features of early AD, including synapse loss and hyperexcitability. Moreover, they indicate that astrocytes play a protective role in preserving synapses, particularly during short-term exposure to low concentrations of toxic Aβ. Future work is needed to elucidate the role of astrocyte-mediated synapse phagocytosis in response to chronic Aβ exposure.