ASTROCYTE-NEURON INTERACTIONS ARE PROTECTIVE AGAINST SYNAPSE LOSS IN AN EX VIVO MODEL OF EARLY-STAGE OF ALZHEIMER’S DISEASE

Synapse loss begins early in Alzheimer’s disease (AD) and strongly correlates with cognitive decline. Data from human AD brains and ex vivo models show increased phagocytosis of synapses from astrocytes. It is unclear, however, whether this is a protective mechanism by removing dysfunctional synapses or a detrimental process, either by targeting connections essential for normal function or by reducing the pool of synapses available to compensate for pathological synapse loss.
Here, we address these questions in organotypic mouse brain slices challenged with Aβ-immunodepleted (17.3pM Aβ40, <0.9pM Aβ42) or mock-immunodepleted (52.5pM Aβ40, 31.5pM Aβ42) human AD brain homogenate (ADBH). Synaptic structure and activity are monitored with multiphoton fluorescence thanks to mScarlet/jGCaMP7b expression in CA1 pyramidal neurons, and ECFP in astrocytes.
We demonstrate that Aβ+ ADBH induces a significant increase in the frequency of synaptic calcium events and synapse loss, with a significant difference between the rate of change in synaptic activity of surviving versus lost synapses at 24h. We found that synapses contacted by astrocytes were significantly more likely to survive at 24h after Aβ+ ADBH challenge. Our data suggest that this protective role acts downstream of activity changes and is mediated, at least in part, by the removal of excess glutamate, and reducing the synaptic levels of externalised phosphatidyl serine.
By effectively reproducing key features of early AD, including synapse loss and hyperexcitability, our experiments highlight a protective role for astrocytes in maintaining synapses. Further work will elucidate astrocytes phagocytosis in continued presence of Aβ.