TRANSGLUTAMINASE CATALYZES THE FORMATION OF SODIUM DODECYL SULFATE-INSOLUBLE, ALZ-50-REACTIVE POLYMERS OF TAU

Paired helical filaments, a constituent of neurofibrillary tangles in Alzheimer's disease, consist primarily of the microtubule-associated p rotein tau. However, the process by which the detergent-insoluble fila ments of the neurofibrillary tangles are formed from soluble tau remai ns unknown. Here, we present a potential mechanism for the abnormal ag gregation Of tau in Alzheimer's disease: the covalent cross-linking of tau by the enzyme transglutaminase. Macromolecular complexes of tau, formed in the presence of transglutaminase, were found to be insoluble in ionic detergent, beta-mercaptoethanol, guanidine-HCI, and urea and , furthermore, demonstrated an increased immunoreactivity with the mon oclonal antibody Alz-50. Electron microscopic studies revealed that ta u cross-linked by transglutaminase has a defined filamentous structure . These results indicate that transglutaminase, the activity of which has been shown to increase during programmed cell death, may play a ro le in the formation of pathology associated with Alzheimer's disease.