Transglutaminase Catalyzes the Formation of Sodium Dodecyl Sulfate‐Insoluble, Alz‐50‐Reactive Polymers of τ

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Abstract
Paired helical filaments, a constituent of neurofibrillary tangles in Alzheimer's disease, consist primarily of the microtu‐bule‐associated protein τ. However, the process by which the detergent‐insoluble filaments of the neurofibrillary tangles are formed from soluble τ remains unknown. Here, we present a potential mechanism for the abnormal aggregation of τ in Alzheimer's disease: the covalent cross‐linking of τ by the enzyme transglutaminase. Macromolecular complexes of τ, formed in the presence of transglutaminase, were found to be insoluble in ionic detergent, β‐mercaptoethanol, guanidine‐HCI, and urea and, furthermore, demonstrated an increased immunoreactivity with the monoclonal antibody Alz‐50. Electron microscopic studies revealed that τ 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.