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 protein tau. However, the process by which the detergent-insoluble filaments of the neurofibrillary tangles are formed from soluble tau remains unknown. Here, we present a potential mechanism for the abnormal aggregation 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-HCl, and urea and, furthermore, demonstrated an increased immunoreactivity with the monoclonal antibody Alz-50. Electron microscopic studies revealed that tau 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 role in the formation of pathology associated with Alzheimer's disease.
Dudek
S M
SM
Department of Psychiatry and Behavioral Neurobiology, University of Alabama, Birmingham 35294-0017.
Johnson
G V
GV
D000818:Animals; D000911:Antibodies, Monoclonal; D001921:Brain / Q000378:metabolism; D002384:Catalysis; D002417:Cattle; D003432:Cross-Linking Reagents / Q000494:pharmacology; D015151:Immunoblotting; D046911:Macromolecular Substances; D008854:Microscopy, Electron; D008970:Molecular Weight; D011108:Polymers; D012967:Sodium Dodecyl Sulfate; D012995:Solubility; D011503:Transglutaminases / Q000378:metabolism* / Q000494:pharmacology; D016875:tau Proteins / Q000096:biosynthesis* / Q000737:chemistry*
D000911:Antibodies, Monoclonal; D003432:Cross-Linking Reagents; D046911:Macromolecular Substances; D011108:Polymers; D016875:tau Proteins; D012967:Sodium Dodecyl Sulfate; D011503:Transglutaminases