Abstract
Protein misfolding and the formation of stable insoluble protein complexes by self-interacting proteins, in particular amyloid-β and tau protein, play a central role in the pathogenesis of Alzheimer's disease (AD). Unfortunately, the underlying mechanisms that trigger the misfolding of self-interacting proteins that eventually results in formation of neurotoxic dimers, oligomers, and aggregates remain unclear. Elucidation of the driving forces of protein complex formation in AD is of crucial importance for the development of disease-modifying therapies. Tissue transglutaminase (tTG) is a calcium-dependent enzyme that induces the formation of covalent ε-(γ-glutamyl)lysine isopeptide bonds, which results in both intra- and intermolecular protein cross-links. These tTG-catalyzed intermolecular cross-links induce stable, rigid, and insoluble protein complexes, whereas intramolecular cross-links change the conformation of proteins. Inhibition of tTG-catalyzed cross-linking counteracts the formation of protein aggregates, as observed in disease-models of other protein misfolding diseases, in particular Parkinson's and Huntington's diseases. Although data of tTG activity in AD models is limited, there is compelling evidence from both in vitro and postmortem human brain tissue of AD patients that point toward a crucial role for tTG in the pathogenesis of AD. Here, we review these data on the role of tTG in the initiation and development of protein aggregates in AD, and discuss the possibility to use inhibitors of the cross-linking activity of tTG as a new therapeutic approach for AD.