Liquid-liquid phase separation of tau in Alzheimer's disease

Tau is a microtubule-associated protein that plays a central role in neuronal stability and axonal transport. However, under pathological conditions, it undergoes structural and functional changes that lead to Alzheimer's disease (AD) and related tauopathies. Recent evidence highlights liquid-liquid phase separation (LLPS) as a critical mechanism underlying tau aggregation and the subsequent formation of neurofibrillary tangles (NFTs). This chapter explores the properties of tau, including its intrinsically disordered nature, isoforms, and post-translational modifications (PTMs), that predispose it to LLPS. We discuss the thermodynamic and molecular principles of LLPS, with emphasis on the interplay between multivalent interactions, crowding effects, RNA binding, and cofactors that modulate the formation of tau condensates. Special attention is given to the transition from dynamic, reversible tau droplets to irreversible fibrillar assemblies. The chapter further examines how truncation and PTM cross-talk alter the phase behavior and aggregation propensity of tau. Cellular implications of tau LLPS, including its role in stress granules, synaptic dysfunction, and seeding of NFTs, are also analyzed. Finally, we highlight the regulatory roles of chaperones, metal ions, and interacting proteins and underscore the therapeutic potential of targeting tau phase separation. Together, this synthesis positions the LLPS of tau as a pivotal event in AD pathogenesis and a promising target for therapeutic intervention.