Activation of STAT3 Regulates Reactive Astrogliosis and Neuronal Death Induced by A beta O Neurotoxicity

Amyloid-beta oligomers (A beta O) have been proposed as the most potent neurotoxic and inflammation inducers in Alzheimer's disease (AD). A beta O contribute to AD pathogenesis by impairing the production of several cytokines and inflammation-related signaling pathways, such as the Janus kinases/signal transducer of transcription factor-3 (JAK/STAT3) pathway. STAT3 modulates glial activation, indirectly regulates A beta deposition, and induces cognitive decline in AD transgenic models. However, in vivo studies using an A beta O microinjection rat model have not yet explored STAT3 role. The main purpose of this study was to elucidate if a single microinjection of A beta O could promote an increased expression of STAT3 in glial cells favoring neuroinflammation and neurodegeneration. We designed a model of intrahippocampal microinjection and assessed glial activation, cytokines production, STAT3 expression, and neurodegeneration in time. Our results showed robust expression of STAT3 in glial cells (mainly in astrocytes) and neurons, correlating with neuronal death in response to A beta O administration. A STAT3 inhibition assay conducted in rat primary hippocampal cultures, suggested that the induction of the transcription factor by A beta O in astrocytes leads them to an activation state that may favor neuronal death. Notwithstanding, pharmacological inhibition of the JAK2/STAT3 pathway should be focused on astrocytes because it is also essential in neurons survival. Overall, these findings strongly suggest the participation of STAT3 in the development of neurodegeneration.