Transglutaminase(TGase) catalyses the crosslink of proteins by forming ε-(γ-glutamyl) lysine isopeptide bonds and requires the binding of Ca2+ for its activity. In mammals, eight distinct TGase isoenzymes have been identified. Tissue transglutaminase (tTGase), also known as TGase 2, has four distinct domains: N-terminal β-sandwich, catalytic core and two C-terminal β-barrel domains. tTGase may have a role in cell death, cell proliferation, cell differentiation, and receptor-mediated endocytosis. In the Alzheimer’s disease brain, the elevated tTGase activity is manifested by polymerization of a number of proteins, including Aβ peptide, β-amyloid precursor protein and the tau protein, with formation of neurofibrillary tangles.