Transglutaminase facilitates the formation of polymers of the β-amyloid peptide

One of the major pathological characteristics of Alzheimer's disease is the increased number of amyloid-containing senile plaques within the brain. The dense cores of these plaques are composed primarily of highly insoluble aggregates of a 39–43-residue peptide referred to as the β-amyloid peptide (βA). The mechanisms by which these insoluble extracellular deposits of βA are formed remain unknown. In this study, the cross-linking of βA by the calcium-dependent enzyme, transglutaminase 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 βA (1–40) was readily cross-linked by transglutaminase, forming multimers in a time-dependent fashion. Furthermore, a second peptide with a substitution similar to that in the Dutch-type hereditary amyloidosis mutation (Glu²² to Gln) was also found to be a substrate fro transglutaminase. Since transglutaminase covalently cross-links proteins through glutamine residues, it is suggested that transglutaminase contributes to amyloid deposition in Dutch-type hereditary amyloidosis, and possibl Alzheimer's disease.