Although the recent approval of anti-amyloid therapies has marked an important milestone for Alzheimer’s disease, their modest clinical benefit underscores the need for alternative disease-modifying strategies. Converging evidence identifies Tau as a central mediator of synaptic dysfunction and neurodegeneration, not only through toxic gain-of-function mechanisms driven by aggregation, but also through loss of its physiological roles in microtubule stabilization and synaptic regulation. Our work using conditional Tau models has demonstrated that both pathological accumulation and Tau depletion contribute to disease progression, revealing that disrupted Tau homeostasis—rather than simple overexpression—is a critical determinant of neuronal vulnerability. Building on these findings, this project aims to develop an innovative RNA-targeting therapeutic strategy to precisely modulate human Tau expression, restoring its functional balance while preventing pathological buildup. By integrating mechanistic insights from our conditional models with translational therapeutic development, we seek to establish a versatile and potentially transformative approach applicable across tauopathies and other Tau-associated brain disorders.