Reactive Astrocytes with Reduced Function of Glutamate Transporters in the App(NL-G-F) Knock-in Mice.

Alzheimer's disease (AD) is associated with synaptic and memory dysfunction. One of the hallmarks of AD 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. Here, we used an App knock-in AD model (App(NL-G-F)) 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 synaptosomes, we found that App(NL-G-F) 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(NL-G-F) mice, measured as electrophysiological recordings of glutamate transporter currents, was severely impaired compared to WT animals. The reduction of glutamate uptake by astrocytes cannot be explained by GLT-1 protein levels, which were unchanged in synaptosomes and hippocampus of App(NL-G-F) mice. Our data suggest that astrocytic glutamate transporters are affected by excess Aβ42 in the brain contributing to synaptic dysfunction in the hippocampus. This data contributes to the notion of restoring astrocyte synaptic function as a potential therapeutic strategy to treat AD.