Exon 3 insert of tau protein in neurodegenerative diseases

Microtubule-associated protein tau is the major component of the filamentous neurofibrillary lesions of Alzheimer's disease (AD) and other tauopathies. Recently, it has been reported that tau isoforms lacking both N-terminal exon 2 and exon 3 do not form straight filament- or paired helical filament-like filaments in vitro, and that the N-terminal exons facilitate assembly of full-length tau. However, neuropathological and biological studies on the N-terminal region of tau protein in human tissue have been limited. We performed a biochemical study on the abnormally phosphorylated tau in brains affected by AD and corticobasal degeneration (CBD), and an immunohistochemical study on tau-positive structures in neurodegenerative diseases, to clarify whether tau with the exon 3 insert was present in abnormal tau-positive structures. On immunoblots of sarkosyl-insoluble tau, anti-exon 3 antibody (anti-E3 Ab) recognized two bands of 68 and 72 kDa in AD and only one band of 72 kDa in CBD. Immunohistochemically, anti-E3 Ab recognized most parts of the neurofibrillary tangles (NFT) in AD and Pick bodies in Pick's disease. In progressive supranuclear palsy (PSP) and CBD, most NFT and pretangles were positive for anti-E3 Ab, as were a small number of glial inclusions. These results indicate that abnormally phosphorylated tau containing the exon 3 insert is present in both PSP and CBD brain, and that CBD cannot be distinguished from PSP by immunoreactivity for anti-E3 Ab. Although most intraglial inclusions were negative for anti-E3 Ab, a few were positive. Therefore, tau isoforms containing the exon 3 insert are expressed at low levels in glial cells.