Effect of transglutaminase on Aβ_1-40 fibril formation and neurotoxicity

The involvement of tissue transglutaminase (tTG) in the process of senile plaque (SP) formation in Alzheimer's disease (AD) brain has been investigated by several groups recently. It was proposed that tTG might play a role in the formation of insoluble deposits in AD, but no direct evidence on the ability of tTG to facilitate the aggregation of amyloid β-peptide (Aβ) was presented. Here we demonstrate that the interaction of Aβ_1-40 with tTG formed higher molecular weight aggregates of the peptide but prevented Aβ fibril formation, and we propose possible configurations of tTG-induced Aβ cross-links which may play a role in Aβ fibrillization. We also demonstrate that co-incubation of Aβ_1-40 with tTG did not affect the toxicity of the peptide. Consistent with findings from several laboratories, these results suggest that fibril formation is not necessarily related to peptide toxicity. Furthermore our results suggest that Aβ toxicity found in cell culture and fibril formation in Aβ solution are not directly related to tTG-Aβ interaction.