Investigation of AGE, their receptor and NF-KB activation and apoptosis in patients with ATTR and Gelsolin amyloidosis

Abstract

Background: Transthyretin (TTR) and gelsolin amyloidoses represent two types of hereditary amyloidosis in which point mutations in the respective protein lead to conformational changes of the protein with subsequent amyloid fibril formation. Material and methods: Tissues from Finnish gelsolin amyloid patients, Danish, Japanese and Swedish ATTR patients were immunostained for AGE, RAGE, NF-κB, PARP, and caspases 3 and 8. Results: Amyloid was heavily deposited in myocard, kidney and gastrointestinal tract of all patients. Immunoreactive areas to AGE and RAGE were detected in the heart, kidney, rectum, gut and appendix. AGE and RAGE were well co-localised with amyloid deposits. In five out of 14 patients neither NF-κB activation nor induction of apoptosis marked by positive immunostaining for NF-κB, PARP, or caspases 3 and 8 was found, and markers of apoptosis were detected in some samples without accompanying NF-κB activation. Conclusion: Our results suggest that both AGE and RAGE may have a common role in evolution of TTR and gelsolin-related amyloidoses. Apart from AGE-RAGE interactions both amyloid proteins may directly bind to RAGE and result in cellular perturbations; but in view of this study cytotoxic effects other than those triggered by activation of NF-κB or apoptosis should be considered