A pathological phosphorylation pattern enhances tau cooperativity on microtubules and facilitates tau filament assembly

Abstract Phosphorylation of the microtubule-associated protein tau plays important roles in both normal physiology and disease. While tau phosphorylation levels are similarly elevated in processes such as fetal development and hibernation and in pathological states like Alzheimer’s disease, the pattern of phosphorylation differs between these contexts. Whether distinct phosphorylation patterns differentially impact tau’s function on microtubules and its propensity to form neurofibrillary tangles (NFTs) has remained unclear. Here we investigated how differential phosphorylation affects microtubule binding, cooperative tau envelope formation, and NFT-relevant filament assembly. Consistent with prior work, phosphorylation decreases tau’s overall microtubule affinity. However, we find that phosphorylation more dramatically impacts cooperativity between tau molecules during envelope formation. Strikingly, the specific pattern of phosphorylation, rather than overall level, strongly promotes tau filament assembly in vitro. These findings provide insights into how tau phosphorylation modulates its physiological microtubule interactions and its pathoconversion into NFTs.