The Cellular Environment Guides Self‐Assembly and Structural Conformations of Microtubule‐Associated Protein Tau (MAPT)

Abstract In neurodegenerative tauopathies, such as Alzheimer's disease (AD), microtubule‐associated protein tau (MAPT/tau) transitions from a soluble form to insoluble, filamentous lesions inside affected neurons. During this process, tau adopts a range of physical configurations: from misfolded monomers to higher‐order oligomers and fibrils. Tau aggregation is also associated with changes in post‐translational modifications (PTMs), such as ubiquitination, oxidation, glycation, hyper‐phosphorylation and acetylation, which collectively produce an impressive range of possible tau proteoforms. Many of these tau proteoforms are highly cationic and unlikely to self‐assemble without neutralization of their charges. Indeed, tau fibrils from patients contain anionic biomacromolecules and bound proteins, suggesting that cytosolic components contribute to fibrilligenesis. Here, we review what is known about how the cytosol impacts tau's aggregation pathways. We also speculate that the composition of each brain region ( e. g ., redox state, tau proteoforms, levels of permissive polyanions, etc .) might play an active role in shaping the structure of the resulting tau fibrils. Although much remains to be discovered, a greater understanding of the role of the cytosol on tau self‐assembly might lead to identification of new therapeutic targets.