Interaction between tissue transglutaminase and amyloid-beta: Protein-protein binding versus enzymatic crosslinking

Self-interaction, chaperone binding and posttranslational modification of amyloid-beta (A beta) is essential in the initiation and propagation of A beta aggregation. Aggregation results in insoluble A beta deposits characteristic of Alzheimer's disease (AD) brain lesions, i.e. senile plaques and cerebral amyloid angiopathy. Tissue transglutaminase (tTG) is a calcium-dependent enzyme that catalyzes posttranslational modifications including the formation of covalent epsilon-(gamma-glutamyl)ysine isopeptide bonds (molecular crosslinks), and colocalizes with A beta deposits in AD. Two independent groups recently found that apart from the induction of A beta oligomerization, the blood-derived transglutaminase member FXIIIa forms stable protein-protein complexes with A beta independent of the transamidation reaction. Here, we investigated whether also tTG forms rigid protein complexes with A beta in the absence of catalytic activation. We found that both A beta(1.40) and A beta(1-42) are substrates for tTG-catalyzed crosslinking. In addition, in the absence of calcium or the presence of a peptidergic inhibitor of tTG, stable tTG-A beta(1.40) complexes were found. Interestingly, the stable complexes between tTG and A beta(1-)(40), were only found at 'physiological' concentrations of A beta(1.40). Together, our data suggest that depending on the A beta species at hand, and on the concentration of A beta, rigid protein-complexes are formed between tTG and A beta(1-40) without the involvement of the crosslinking reaction.