Microtubule-associated protein tau is a major antigenic component of paired helical filaments in Alzheimer disease

The detailed protein composition of the paired helical filaments (PHF) that accumulate in human neurons in aging and Alzheimer disease is unknown. However, the identity of certain components has been surmised by using immunocytochemical techniques. Whereas PHF share epitopes with neurofilament proteins and microtubule-associated protein (MAP) 2, we report evidence that the MAP tau (τ ) appears to be their major antigenic component. Immunization of rabbits with NaDodSO4-extracted, partially purified PHF (free of normal cytoskeletal elements, including τ ) consistently produces antibodies to τ but not, for example, to neurofilaments. Such PHF antibodies label all of the heterogeneous fetal and mature forms of τ from rat and human brain. Absorption of PHF antisera with heat-stable MAPs (rich in τ ) results in almost complete loss of staining of neurofibrillary tangles (NFT) in human brain sections. An affinity-purified antibody to τ specifically labels NFT and the neurites of senile plaques in human brain sections as well as NaDodSO4-extracted NFT. τ -Immunoreactive NFT frequently extend into the apical dendrites of pyramidal neurons, suggesting an aberrant intracellular locus for this axonal protein. τ and PHF antibodies label τ proteins identically on electrophoretic transfer blots and stain the gel-excluded protein representing NaDodSO4-insoluble PHF in homogenates of human brain. The progressive accumulation of altered τ protein in neurons in Alzheimer disease may result in instability of microtubules, consequent loss of effective transport of molecules and organelles, and, ultimately, neuronal death.