Intracellular deposits of amyloid-beta influence the ability of human iPSC-derived astrocytes to support neuronal function

Background: Astrocytes are crucial for maintaining brain homeostasis and synaptic function, but are also tightly connected to the pathogenesis of Alzheimer's disease (AD). Our previous data demonstrate that astrocytes ingest large amounts of aggregated amyloid-beta (A beta), but then store, rather than degrade the ingested material, which leads to severe cellular stress. However, the involvement of pathological astrocytes in AD-related synaptic dysfunction remains to be elucidated. Methods: In this study, we aimed to investigate how intracellular deposits of A beta in astrocytes affect their interplay with neurons, focusing on neuronal function and viability. For this purpose, human induced pluripotent stem cell (hiPSC)-derived astrocytes were exposed to sonicated A beta(42) fibrils. The direct and indirect effects of the A beta-exposed astrocytes on hiPSC-derived neurons were analyzed by performing astrocyte-neuron co-cultures as well as additions of conditioned media or extracellular vesicles to pure neuronal cultures. Results: Electrophysiological recordings revealed significantly decreased frequency of excitatory post-synaptic currents in neurons co-cultured with A beta-exposed astrocytes, while conditioned media from A beta-exposed astrocytes had the opposite effect and resulted in hyperactivation of the synapses. Clearly, factors secreted from control, but not from A beta-exposed astrocytes, benefited the wellbeing of neuronal cultures. Moreover, reactive astrocytes with A beta deposits led to an elevated clearance of dead cells in the co-cultures. Conclusions: Taken together, our results demonstrate that inclusions of aggregated A beta affect the reactive state of the astrocytes, as well as their ability to support neuronal function.