Artificial microRNAs targeting Tau enable post-symptomatic functional recovery in aged tauopathy mice

Tauopathies are a group of neurodegenerative disorders, including Alzheimer's disease, frontotemporal dementia, and progressive supranuclear palsy, characterized by the pathological accumulation of tau protein. While tau reduction has emerged as a promising disease-modifying strategy, most preclinical studies have focused on preventive approaches, and the therapeutic potential after clinical onset remains largely unexplored. This limitation is critical, as patients are typically diagnosed after symptoms emerge. Furthermore, global tau suppression may disrupt physiological tau functions and lead to adverse effects, underscoring the need for targeted interventions. RNA-based therapies, particularly microRNA (miRNA)-mediated silencing, offer high specificity, versatility, and sustained target knockdown. Here, we developed artificial microRNAs (Tau-miRNAs) designed for site-directed expression to selectively reduce tau levels in vulnerable brain regions, thereby minimizing off-target effects. We tested the efficacy of Tau-miRNAs in a tauopathy mouse model at advanced disease stages, delivering them into the prefrontal cortex after cognitive and electrophysiological deficits had developed. This post-symptomatic intervention led to long-term improvements in memory, restoration of neuronal firing properties, and reduced pathological tau at synapses. Our findings highlight the therapeutic potential of spatially targeted RNA-based tau-lowering strategies for late-stage intervention in tauopathies, addressing a critical unmet need in the treatment of these devastating disorders.