Tau Liquid-Liquid Phase Separation in Alzheimer's Disease: Mechanisms, Pathogenesis, and Therapeutic Implications.

Tau protein undergoes liquid-liquid phase separation (LLPS), forming dynamic condensates that act as intermediates in the transition to neurofibrillary tangles in Alzheimer's disease (AD). This review highlights tau's dynamic and reversible LLPS behavior, an underexplored aspect of tau's role, particularly as an early pathogenic driver in AD. We summarize the molecular mechanisms and regulatory factors governing tau LLPS, with a focus on its physiological functions in microtubule stability, synaptic activity, and cellular stress responses. Additionally, we discuss how metal ions, RNA, and neurodegenerative cofactors influence tau's phase behavior in a cell-type-specific manner. Emerging strategies targeting tau LLPS-such as nanobodies, AAV-based delivery, engineered degradation platforms, and CRISPR tools-show promise for early, reversible intervention. We also explore the potential of LLPS-informed biomarkers for diagnosing and monitoring disease progression. Overall, LLPS provides a dynamic, targetable framework linking early AD pathogenesis with therapeutic innovation, opening opportunities for earlier intervention and more effective treatment strategies.