Hyperphosphorylation of the microtubule-associated protein tau (tau) induces its self-assembly into paired helical filaments (PHF) and straight filaments (SF). Abnormally hyperphosphorylated tau (AD P-τ) from Alzheimer's disease (AD) brain self-aggregates into PHF-like structures under specific conditions. In vitro dephosphorylation inhibits this self-assembly, while hyperphosphorylation promotes the formation of PHF and SF by neutralizing inhibitory basic charges in flanking regions. All six tau isoforms self-assemble into PHF/SF when hyperphosphorylated, and the microtubule binding domains/repeats can also self-assemble into PHF. The study shows that tau self-assembly is driven by interactions between microtubule binding domains, with hyperphosphorylation facilitating the formation of PHF/SF by neutralizing inhibitory charges. Tauopathies, including AD, are characterized by neurofibrillary tangles of PHF/SF and amyloid β plaques. Hyperphosphorylation of tau is a key factor in the pathogenesis of these diseases, as it promotes the self-assembly of tau into pathological filaments. The study also highlights the role of tau's microtubule binding domains and the impact of hyperphosphorylation on its structural properties. The findings suggest that abnormal hyperphosphorylation of tau is critical in the development of neurofibrillary degeneration in AD and other tauopathies.Hyperphosphorylation of the microtubule-associated protein tau (tau) induces its self-assembly into paired helical filaments (PHF) and straight filaments (SF). Abnormally hyperphosphorylated tau (AD P-τ) from Alzheimer's disease (AD) brain self-aggregates into PHF-like structures under specific conditions. In vitro dephosphorylation inhibits this self-assembly, while hyperphosphorylation promotes the formation of PHF and SF by neutralizing inhibitory basic charges in flanking regions. All six tau isoforms self-assemble into PHF/SF when hyperphosphorylated, and the microtubule binding domains/repeats can also self-assemble into PHF. The study shows that tau self-assembly is driven by interactions between microtubule binding domains, with hyperphosphorylation facilitating the formation of PHF/SF by neutralizing inhibitory charges. Tauopathies, including AD, are characterized by neurofibrillary tangles of PHF/SF and amyloid β plaques. Hyperphosphorylation of tau is a key factor in the pathogenesis of these diseases, as it promotes the self-assembly of tau into pathological filaments. The study also highlights the role of tau's microtubule binding domains and the impact of hyperphosphorylation on its structural properties. The findings suggest that abnormal hyperphosphorylation of tau is critical in the development of neurofibrillary degeneration in AD and other tauopathies.