Tissue transglutaminase (TGase) has been implicated in a number of cellular processes and disease states, where the enzymatic actions of TGase may serve in both, cell survival and apoptosis. To date, the precise functional properties of TGase in cell survival or cell death mechanisms still remain elusive. TGasemediated cross-linking has been reported to account for the formation of insoluble lesions in conformational diseases. We report here that TGase induces intramolecular cross-linking of ␤-amyloid peptide (A␤), resulting in structural changes of monomeric A␤. Using high resolution mass spectrometry (MS) of cross-linked A␤ peptides, we observed a shift in mass, which is, presumably associated with the loss of NH 3 due to enzymatic transamidation activity and hence intramolecular peptide cross-linking. We have observed that a large population of A␤ monomers contained an 0.984 Da increase in mass at a glutamine residue, indicating that glutamine 15 serves as an indispensable substrate in TGase-mediated deamidation to glutamate 15. We provide strong analytical evidence on TGasemediated A␤ peptide dimerization, through covalent intermolecular cross-linking and hence the formation of A␤ 1-40 dimers. Our in depth analyses indicate that TGase-induced post-translational modifications of A␤ peptide may serve as an important seed for aggregation.

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