Key Physicochemical and Biological Factors of the Phase Behavior of Tau

Study Summary

Recent findings have garnered a substantial amount of attention towards tau based on its pathological contribution in neurodegenerative diseases, such as Alzheimer’s disease (AD). Studies investigating the structure and aggregation of tau under various in vitro and in vivo conditions have revealed its intrinsically disordered structures and amyloidogenesis process.

The aggregation behavior of tau is strongly dependent on the experimental conditions due to the high sensitivity of both the soluble tau conformations and amyloid nucleation process towards its surrounding environments.

We reviewed and discussed (i) the effects of different physicochemical and biological factors as well as intermolecular interactions with various molecular chaperones on tau aggregation, (ii) context-dependent liquid-liquid phase separation of tau and its amyloidogenic transformation, and (iii) the utility of the phase diagram in comprehending the phase transition and separation of proteins.

Population aging is a major global trend of the 21st century. Age-related tauopathies, including Alzheimer’s and Pick’s diseases, are expected to become more prevalent, placing heavy burdens on social welfare. A pathological hallmark of tauopathies is the abnormal aggregation of soluble tau proteins to insoluble amyloid fibrils in neurons. In addition to this irreversible liquid-to-solid phase transition, tau undergoes reversible liquid-liquid phase separation (LLPS) in cells, important for the function of axonal microtubule bundles and the pathogenic aggregation of tau. Therefore, gaining a better understanding of how tau self-assembles at the molecular level is critical for developing effective therapeutic agents for the treatment and prevention of tauopathies. We provide an overview of how key physicochemical and biological factors control the aggregation of tau and briefly discuss the recent findings of LLPS.

[Figure 1] Phase behavior of tau under various conditions

Top: summary of factors affecting the association and aggregation of tau. Bottom: illustration of context-dependent structural changes of tau as well as its phase transition and separation. Blue and red arrows indicate the soluble and functional tau (left) and the insoluble tau aggregation (right), respectively. Functions, various molecular species, and key reaction steps are labeled.

[Figure 2] Phase diagrams of the phase transition and separation of proteins

Phase diagram of the aggregation (i.e., phase transition) of beta-2 microglobulin. Cartoons of soluble monomers and insoluble aggregates [i.e., amyloid fibrils (yellow) and amorphous aggregates (green)] are shown. (Right) Phase diagram of the LLPS of tau.