Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is associated with synaptic and memory dysfunction. A pathological hallmark of the disease is reactive astrogliosis, with reactive astrocytes surrounding amyloid plaques in the brain. Astrocytes have also been shown to be actively involved in disease progression, nevertheless, mechanistic information about their role in synaptic transmission during AD pathology is lacking. Astrocytes maintain synaptic transmission by taking up extracellular glutamate during synaptic activity through astrocytic glutamate transporter GLT-1, but its function has been difficult to measure in real-time in AD pathology.

Method: In this study, we used an App knock-in AD model (App) carrying the Swedish, Arctic and Beyreuther mutations associated with AD and exhibiting AD-like Aβ plaque deposition and memory impairment. Using immunohistochemistry, patch-clamp of astrocytes, and western blot from tissue and FACS isolated astrocytes.

Result: We found that App mice at 6-8 months of age have astrocytes with clearly altered morphology compared to wild-type (WT). Moreover, astrocyte glutamate clearance function in App mice, measured as electrophysiological recordings of glutamate transporter currents, was severely impaired compared to WT animals. We suggest that the loss of function of GLT-1 is not related to altered protein levels since no changes in GLT-1 levels in synaptosomes nor FACS-isolated astrocytes from App mice were found. This phenotype can potentially alter synaptic transmission and/or contribute to glutamate excitotoxicity.

Conclusion: Our data suggest that astrocytic glutamate transporters are affected by excess Aβ42 in the brain contributing to synaptic dysfunction in the hippocampus. Thus, our data indicate that restoring astrocyte synaptic function could be a potential therapeutic strategy to treat AD.