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

## TL;DR

Astrocytes protect synapses from damage caused by amyloid-beta in a mouse model of early Alzheimer's disease.

## Contribution

This study demonstrates that astrocytes protect synapses from Aβ-induced degeneration through glutamate removal in an ex vivo Alzheimer's model.

## Key findings

- Aβ-containing homogenate causes spine loss and increased synaptic calcium events in mouse brain slices.
- Dendritic spines near astrocytic processes are more likely to survive Aβ exposure.
- Astrocyte protection of synapses is partially mediated by glutamate transporter activity.

## Abstract

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.

Alzheimer's disease (ad) is the most common cause of dementia, affecting over 35 million people worldwide. A key feature of ad is the loss of synapses—the connections between brain cells—which strongly correlates with cognitive decline. We sought to investigate the role of astrocytes in mouse organotypic cultures challenged with brain homogenate (BH) from ad patients to model early Aβ insult. Our results indicate that Aβ aggregates present in Aβ+ BH are responsive for increased synaptic activity, externalisation of signal lipid phosphatidyl serine (ptdSer) and synapse loss. We propose that glutamate toxicity due to hyperactivity can, at least in part, mediate the observed synapse loss. Astrocytes were found to prevent synapse loss and reduce ptdSer exposure in their proximity, but had no effect on activity reduction, suggesting that their effect lies downstream of changes in activity and involves glutamate removal via astrocytic glutamate transporters.