Neuronal PARIS-STAT3 axis drives tau pathology and glial activation in Alzheimer's disease

PARIS, a substrate of Parkin, accumulates in Parkinson's disease and promotes disease progression. Here, we demonstrate that PARIS also contributes to Alzheimer's disease by elevating STAT3 transcriptional activity, thereby inducing tau pathology, hippocampal atrophy, and glial activation. Genetic depletion of Paris reduced tau phosphorylation and cognitive decline in tauopathy mice, whereas neuron-specific PARIS overexpression caused tau accumulation, gliosis, and memory impairment. In contrast, astrocyte-specific overexpression did not induce pathology, indicating that PARIS acts in neurons to drive tau phosphorylation and glial activation. The pathological features induced by neuronal PARIS overexpression were rescued by STAT3 inhibition, demonstrating that PARIS-STAT3 signaling underlies these effects. Moreover, Paris knockout did not alter pathology in the amyloid-driven mouse model, highlighting specificity for tau pathology. Together, these findings reveal PARIS as a neuronal regulator of STAT3 signaling that exacerbates tau-mediated neurodegeneration and identify the PARIS-STAT3 pathway as a potential therapeutic target in Alzheimer's disease.