Structure of NFT: Biochemical Approach.

Neurofibrillary tangle (NFT), bundle of paired helical filaments in neurons is one of the defining features of Alzheimer's disease (AD) and their spreads well correlate with disease symptoms and progression of AD. Using the unusual insolubility, NFTs were partially purified and the antibodies were produced. Characterization of these antibodies and biochemical studies of tau in AD revealed that a hyperphosphorylated tau protein is the major component of NFTs. In 1998, mutations in the tau gene were discovered in FTDP-17, demonstrating that abnormalities of tau cause accumulation of tau and neurodegeneration. Abnormal tau pathology occurs not only in AD, but also in other neurodegenerative dementing disorders, such as Pick's disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). The tau isoforms accumulated in these inclusions are different among the diseases. Biochemical and proteinchemical analyses of these pathological tau proteins in these tauopathies demonstrated that the protease-resistant cores of the tau aggregates are composed of different microtubule binding regions and distinct between the diseases. Recent Cryo-EM analyses revealed the core structures of tau filaments in AD and PiD, confirming our biochemical observations. Further studies of tau and other abnormal proteins will provide important insights into molecular mechanisms of protein aggregation and prion-like propagation in neurodegenerative diseases.