TRANSGLUTAMINASE FACILITATES THE FORMATION OF POLYMERS OF THE BETA-AMYLOID PEPTIDE

One of the major pathological characteristics of Alzheimer's disease i s the increased number of amyloid-containing senile plaques within the brain. The dense cores of these plaques are composed primarily of hig hly insoluble aggregates of a 39-43-residue peptide referred to as the beta-amyloid peptide (beta A). The mechanisms by which these insolubl e extracellular deposits of beta A are formed remain unknown. In this study, the cross-linking of beta A by the calcium-dependent enzyme, tr ansglutaminase was examined. Transglutaminases are a family of enzymes which are found in brain, and catalyse the cross-linking of specific proteins into insoluble polymers. Synthetic beta A (1-40) was readily cross-linked by transglutaminase, forming multimers in a time-dependen t fashion. Furthermore, a second peptide with a substitution similar t o that in the Dutch-type hereditary amyloidosis mutation (Glu(22) to G ln) was also found to be a substrate for transglutaminase. Since trans glutaminase covalently cross-links proteins through glutamine residues , it is suggested that transglutaminase contributes to amyloid deposit ion in Dutch-type hereditary amyloidosis, and possibly Alzheimer's dis ease.