Microtubule-associated protein tau (phosphorylated form) (Tau (pTau); MAPT (for gene))

Phosphorylated tau is the post-translationally modified form of microtubule-associated protein tau, primarily via phosphorylation at multiple serine, threonine, and tyrosine residues. Physiologically, tau stabilizes neuronal microtubules, enabling axonal transport and maintaining neuron structure. Tau is regulated by both kinases and phosphatases, with phosphorylation shifting its affinity and association with microtubules. Under pathological conditions (notably in Alzheimer's disease and other tauopathies), tau becomes abnormally hyperphosphorylated, leading to weakened microtubule stabilization, detachment from microtubules, mislocalization, and self-assembly into paired helical filaments and neurofibrillary tangles. These aggregated tau forms disrupt cellular transport, contribute to neuronal death, and serve as a pathological hallmark of several neurodegenerative diseases. Phosphorylated tau can also affect nuclear functions, including chromatin organization and DNA protection, and undergoes dynamic phase separation dependent on phosphorylation state. Targeting phosphorylated tau for therapy focuses on preventing its pathological aggregation, modulating phosphorylation via kinase/phosphatase regulators, and promoting clearance. Reliable detection of phosphorylated tau isoforms in CSF and imaging serves as a key biomarker for early diagnosis and disease monitoring. Safety remains a challenge due to tau’s numerous biological roles and the risk of disrupting normal neuronal function.

Other names

Phosphorylated taupTauMAPT (Microtubule-associated protein tau gene)Hyperphosphorylated tauNeurofibrillary tangle tau

Mechanism of action for drugs targeting phosphorylated tau include inhibition of tau phosphorylation (e.g., via kinase inhibitors), inhibition of tau aggregation/fibrillization, promotion of tau clearance, modulation of tau-mediated microtubule stabilization, and enhancement of O-GlcNAc modification to prevent hyperphosphorylation.