Alzheimer disease: from abnormal phosphorylation of tau to neurofibrillary degeneration : K. Iqbal, A. del C. Alonso, C.-X. Gong, S. Khatoon, J.-J. Pei, J.Z. Wang and I. Grundke-Iqbal. New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314 USA

Abstract

The relationship between Alzheimer's disease (AD) and expression of fetal proteins was examined by: (i) determining the phosphate content of tau prepared from fetal brains (F-tau); (ii) comparing F-tau, tau from normal adult human brains (N-tau) and tau from paired helical filaments in AD brains (PHF-tau) for phosphate content; and (iii) testing the reactivity of F-tau with five antibodies known to recognize PHF-tau. The antibodies have been reported to recognize phosphate dependent epitopes at the carboxy-terminal half of the tau molecule. Our data shows that on the average, F-tau contains 7 mol phosphate/mol protein, which is comparable to the phosphate content of PHF-tau, but is 3–4 times higher than that of N-tau. Immunoblotting shows that all of the tested antibodies reacted with F-tau on immunoblots, indicating that F-tau and PHF-tau are phosphorylated at similar sites. A difference between PHF-tau and F-tau is the state of phosphorylation in the Tau-1 epitope, an epitope reactive with a monoclonal anti-tau antibody, Tau-1. This epitope, which is phosphorylated in all PHF-tau, is phosphorylated only in some of the F-tau. The sharing of phosphorylated sites between F-tau and PHF-tau has also been reported by others in studies with antibodies to different and similar phosphorylated epitopes. Together these observations indicate that the extent and the site of phosphorylation in F-tau and PHF-tau tau are similar. Although hyperphosphorylation of tau proteins may be an important step for PHF formation, the absence of AD type pathology in fetal brains containing hyperphosphorylated tau suggests that the transformation of soluble forms of normal tau to AD type cytoskeletal abnormalities may require the presence of other factors.