P4-160: Transglutaminase 1, Transglutaminase 2 and Transglutaminase-catalyzed cross-links colocalize with the pathological lesions in Alzheimer's disease brain

Abstract

Alzheimer's disease (AD) is characterized by several pathological lesions, in particular senile plaques (SPs), cerebral amyloid angiopathy (CAA) and neurofibrillary tangles (NFTs), predominantly consisting of self-aggregated proteins amyloid-beta (Aβ) and tau, respectively. Transglutaminases (TGases) are inducible enzymes, capable of modifying the conformational and/or structural properties of proteins, such as Aβ and tau, by inducing intra- and intermolecular covalent cross-links. Both Aβ and tau are substrates for TGase cross-linking activity, which suggests that TGases play a role in the initiation and persistence of the aggregation process of both Aβ and tau in AD brains. The aim of this study was to investigate the association of Transglutaminase 1 (TG1), Transglutaminase 2 (TG2) and TG-catalyzed cross-links with the pathological lesions of AD. For this purpose, a panel of well-characterized antibodies against TG1, TG2 and the TG-catalyzed cross-links was used in immunohistochemistry. We observed the immunoreactivity for TG1, TG2 and TG-catalyzed cross-links in NFTs. In addition, both TG2 and TG-catalyzed cross-links colocalize with Aβ in SPs. Furthermore, staining of TG2 and TG-catalyzed antibodies was also observed in CAA, although specific colocalization with deposited Aβ in CAA was absent. We conclude that both TG1 and TG2 are present in SPs, CAA and NFTs, and that these enzymes display cross-linking activity in AD lesions. We suggest that both TG1 and TG2 are involved in the initiation and/or persistence of the protein aggregation processes underlying the formation of SPs and CAA, and NFTs in AD brain.