Tau is a major microtubule-associated protein (MAP) in mature neurons, along with MAP1 and MAP2. Its function involves binding to tubulin and promoting microtubule assembly and stabilization. Tau's activity is regulated by its phosphorylation level, with normal adult brain tau containing 2–3 moles of phosphate per mole of protein. Hyperphosphorylation of tau, which is more pronounced in Alzheimer's disease (AD) and related tauopathies, leads to the formation of paired helical filaments (PHF) and straight filaments (SF), resulting in neurofibrillary tangles. Hyperphosphorylated tau in AD is distinguishable from transiently hyperphosphorylated tau by its ability to sequester normal tau and MAPs, disrupt microtubules, and self-assemble into PHF/SF. Abnormally hyperphosphorylated tau in the cytosol is oligomeric and sedimentable, but loses its sequestration ability upon self-assembly. Tau truncation in AD also promotes self-assembly. Mutations in tau, such as those in frontotemporal dementia (FTDP-17), promote abnormal hyperphosphorylation. Inhibition of abnormal hyperphosphorylation of tau is a promising therapeutic target for AD and related tauopathies. Tau mutations in FTDP-17 increase the 4R:3R ratio, leading to neurofibrillary degeneration. Abnormally hyperphosphorylated tau in AD is different from normal and transiently hyperphosphorylated tau, and its cytosolic/oligomeric state is inhibitory to microtubule assembly. However, when self-assembled into PHF/SF, it is less harmful. Tau hyperphosphorylation is associated with neurodegeneration, and its inhibition may offer therapeutic benefits. Tau mutations in FTDP-17 promote abnormal hyperphosphorylation, leading to neurofibrillary tangles. The abnormal hyperphosphorylation of tau in AD is a key factor in neurofibrillary degeneration and microtubule network disruption. Tau mutations in FTDP-17 increase the 4R:3R ratio, leading to neurofibrillary degeneration. Inhibition of abnormal hyperphosphorylation of tau is a promising therapeutic target for AD and related tauopathies.Tau is a major microtubule-associated protein (MAP) in mature neurons, along with MAP1 and MAP2. Its function involves binding to tubulin and promoting microtubule assembly and stabilization. Tau's activity is regulated by its phosphorylation level, with normal adult brain tau containing 2–3 moles of phosphate per mole of protein. Hyperphosphorylation of tau, which is more pronounced in Alzheimer's disease (AD) and related tauopathies, leads to the formation of paired helical filaments (PHF) and straight filaments (SF), resulting in neurofibrillary tangles. Hyperphosphorylated tau in AD is distinguishable from transiently hyperphosphorylated tau by its ability to sequester normal tau and MAPs, disrupt microtubules, and self-assemble into PHF/SF. Abnormally hyperphosphorylated tau in the cytosol is oligomeric and sedimentable, but loses its sequestration ability upon self-assembly. Tau truncation in AD also promotes self-assembly. Mutations in tau, such as those in frontotemporal dementia (FTDP-17), promote abnormal hyperphosphorylation. Inhibition of abnormal hyperphosphorylation of tau is a promising therapeutic target for AD and related tauopathies. Tau mutations in FTDP-17 increase the 4R:3R ratio, leading to neurofibrillary degeneration. Abnormally hyperphosphorylated tau in AD is different from normal and transiently hyperphosphorylated tau, and its cytosolic/oligomeric state is inhibitory to microtubule assembly. However, when self-assembled into PHF/SF, it is less harmful. Tau hyperphosphorylation is associated with neurodegeneration, and its inhibition may offer therapeutic benefits. Tau mutations in FTDP-17 promote abnormal hyperphosphorylation, leading to neurofibrillary tangles. The abnormal hyperphosphorylation of tau in AD is a key factor in neurofibrillary degeneration and microtubule network disruption. Tau mutations in FTDP-17 increase the 4R:3R ratio, leading to neurofibrillary degeneration. Inhibition of abnormal hyperphosphorylation of tau is a promising therapeutic target for AD and related tauopathies.