In vitro neurotoxicity of amyloid β-peptide cross-linked by transglutaminase

Transglutaminase catalyzes the intermolecular cross-linking of peptides between Gln and Lys residues, forming an ε-(γ-glutamyl) lysine bond. Amyloid β-peptide, a major constituent of the deposits in Alzheimer disease, contains Lys16, Lys28, and Gln15 which may act as substrates of transglutaminase. Transglutaminase treatment of amyloid β-peptide (1-28) and amyloid β-peptide (1-40) yielded cross-linked oligomers. Transglutaminase-treated Aβ retarded neurite extension of PC12 cells, and rat cultured neurons of hippocampus and septum, brain areas severely affected by Alzheimer disease, and subsequently caused cell death, whereas the transglutaminase-untreated counterparts did not show harmful effects. The transglutaminase-catalyzed oligomers of amyloid β-peptide and their neurotoxicity may be involved in two characteristics in Alzheimer disease, neuronal degeneration and formation of the insoluble deposits.

AD - Alzheimer disease, Aβ - amyloid β-peptide, DMEM - Dulbecco's modified Eagle's medium, DMEM/F-12-1:1 mixture of DMEM and Ham's F-12 medium, FCS - fetal calf serum, HS - horse serum, PAGE - polyacrylamide gel electrophoresis, MTT - 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, NGF - nerve growth factor, TGase - transglutaminase.