Inhibition of Stat3-mediated astrogliosis ameliorates pathology in an Alzheimer's disease model

Reactive astrogliosis is a hallmark of Alzheimer's disease (AD), but its role for disease initiation and progression have remained incompletely understood. We here show that the transcription factor Stat3 (signal transducer and activator of transcription 3), a canonical inducer of astrogliosis, is activated in an AD mouse model and human AD. Therefore, using a conditional knockout approach, we deleted Stat3 specifically in astrocytes in the APP/PS1 model of AD. We find that Stat3-deficient APP/PS1 mice show decreased ?-amyloid levels and plaque burden. Plaque-close microglia displayed a more complex morphology, internalized more ?-amyloid and upregulated amyloid clearance pathways in Stat3-deficient mice. Moreover, astrocyte-specific Stat3-deficient APP/PS1 mice showed decreased pro-inflammatory cytokine activation and lower dystrophic neurite burden, and were largely protected from cerebral network imbalance. Finally, Stat3 deletion in astrocytes also strongly ameliorated spatial learning and memory decline in APP/PS1 mice. Importantly, these protective effects on network dysfunction and cognition were recapitulated in APP/PS1 mice systemically treated with a preclinical Stat3 inhibitor drug. In summary, our data implicate Stat3-mediated astrogliosis as an important therapeutic target in AD.