Interaction of the receptor for advanced glycation end products (RAGE) with transthyretin triggers nuclear transcription factor kB (NF-kB) activation

Mutated transthyretin (TTR) fibrils are associated with the pathology of fa milial amyloidotic polyneuropathy (FAP), in which extracellular amyloid dep osits lead to degeneration of cells and tissues, in particular neurons of t he peripheral nerve. Here we present evidence that the receptor for advance d glycation end products (RAGE), previously associated with Alzheimer's dis ease, acts as a selective cell surface acceptor site for both soluble and f ibrillar TTR. Immunohistochemical studies demonstrating increased expressio n of RAGE in FAP tissues suggested the relevance of this receptor to TTR-in duced fibrillar pathology. In vitro studies using soluble RAGE showed satur able specific interaction with soluble and fibrillar TTR with a K-d of simi lar to 120 nM. However, no binding was observed when soluble TTR was combin ed with retinol-binding protein, which represents the form in which TTR nor mally circulates in plasma. Specific binding of TTR to RAGE-transfected Chi nese hamster ovary cells (which was completely blocked by anti-RAGE) was ob served, confirming that RAGE could mediate TTR binding to cellular surfaces . RAGE-dependent activation of nuclear transcription factor kB (NF-kB) by T TR fibrils was shown in PC-12 cells stably transfected to overexpress the r eceptor. Furthermore, FAP nerves showed up-regulation of p50, one of the NF -kB subunits, when compared with age-matched controls. From these observati ons we predict that, in vivo, the presence of TTR fibrils associated with c ellular surfaces of FAP patients, by contributing to NF-kB activation, lead s to the pathogenesis of neurodegeneration. Further insights into the conse quences of the interaction of fibrillar TTR with RAGE may therefore provide a better understanding of neurodegeneration associated with FAP.