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

Self-interaction, chaperone binding and posttranslational modification of amyloid-beta (Aβ) is essential in the initiation and propagation of Aβ aggregation. Aggregation results in insoluble Aβ 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 ε-(γ-glutamyl)lysine isopeptide bonds (molecular crosslinks), and colocalizes with Aβ deposits in AD. Two independent groups recently found that apart from the induction of Aβ oligomerization, the blood-derived transglutaminase member FXIIIa forms stable protein-protein complexes with Aβ independent of the transamidation reaction. Here, we investigated whether also tTG forms rigid protein complexes with Aβ in the absence of catalytic activation. We found that both Aβ1-40 and Aβ1-42 are substrates for tTG-catalyzed crosslinking. In addition, in the absence of calcium or the presence of a peptidergic inhibitor of tTG, stable tTG-Aβ1-40 complexes were found. Interestingly, the stable complexes between tTG and Aβ1-40, were only found at 'physiological' concentrations of Aβ1-40. Together, our data suggest that depending on the Aβ species at hand, and on the concentration of Aβ, rigid protein-complexes are formed between tTG and Aβ1-40 without the involvement of the crosslinking reaction.