MECHANISM OF NEUROFIBRILLARY DEGENERATION IN ALZHEIMERS-DISEASE

Neurofibrillary degeneration associated with the formation of intraneu ronal neurofibrillary tangles of paired helical filaments (Pi-IF) and 2.1 nm tau filaments is one of the most characteristic brain lesions o f Alzheimer's disease. The major polypeptides of PHF are the microtubu le associated protein tau. tau in PI-IF is present in abnormally phosp horylated forms. In addition to the PI-IF, the abnormal tau is present in soluble non-PHF form in the Alzheimer's disease brain. The level o f tau in Alzheimer's disease neocortex is severalfold higher than in a ged control brain, and this increase is in the form of the abnormally phosphorylated protein. The abnormally phosphorylated tau does not pro mote the assembly of tubulin into microtubules in vitro, and it inhibi ts the normal tau stimulated microtubule assembly. After in vitro deph osphorylation both PHF and non-PHF abnormal tau stimulate the assembly of tubulin into microtubules. The activities of phosphoseryl/phosphot hreonyl protein phosphatase 2A and nonreceptor phosphotyrosyl phosphat ase(s) are decreased in AD brain. It is suggested that 1. A defect(s) in the protein phosphorylation/dephosphorylation system is one of the early events in the neurofibrillary pathology in AD; 2. A decrease in protein phosphatase activities, at least in part, allows the hyperphos phorylation of tau; and 3. Abnormal phosphorylation and polymerization of tau into PI-IF most probably lead to a breakdown of the microtubul e system and consequently to neuronal degeneration.