MITOTIC PHOSPHOEPITOPES PRECEDE PAIRED HELICAL FILAMENTS IN ALZHEIMERS-DISEASE

We have shown previously that the TG-3 and MPM-2 antibodies recognize phosphoepitopes common to mitosis and degenerating neurons of Alzheime r's disease(AD) brain. Here, we have evaluated their occurrence in hum an brain biopsy tissue, and confirm that they are absent in mature neu rons of adult brain, but reappear during neurodegeneration in AD. The TG-3 epitope appears ahead of the MPM-2 epitope and is distributed thr oughout the neuronal soma. Tau is the major TG-3 antigen in AD brain. The initial localization of MPM-2 immunoreactivity in primary dendrite s, it's robust occurrence in granulovacuolar bodies, and the increased immunoreactivity with 300-350-kDa proteins, suggest MAP1B as a candid ate MPM-2 antigen in AD. Production of mitotic phosphepitopes in more than one type of human neurodegenerative lesion implicates mitotic kin ases as common mediators of neuronal death. Because mitotic phosphoepi topes appear before paired helical filaments, it is suggested that mit otic kinase activation triggers neurofibrillary tangle formation. Futu re studies will need to focus on factors influencing mitotic kinase ac tivity, a point with potential for early diagnosis and disease abrogat ion. (C) 1998 Elsevier Science Inc.