Molecular mechanism of Alzheimer's neurofibrillary degeneration and therapeutic intervention.

Microtubule-associated protein tau is abnormally hyperphosphorylated in the brain of patients with Alzheimer's disease (AD) and the abnormal tau is the major protein subunit of paired helical filaments (PHF). The abnormal phosphorylation of tau probably precedes its polymerization into PHF. The abnormal tau does not bind to tubulin, but competes with tubulin in binding to normal tau and thereby inhibits the assembly of microtubules in the affected neurons. The abnormal tau can be dephosphorylated enzymatically and by this way its microtubule assembly promoting activity can be restored. The activities of protein phosphatases might be decreased in the affected neurons in AD brain, allowing the abnormal hyperphosphorylation of tau. Neurofibrillary degeneration can probably be inhibited by increasing the activities of protein phosphatases in the brain of patients with Alzheimer's disease.