Interaction of the Receptor for Advanced Glycation End Products (RAGE) with Transthyretin Triggers Nuclear Transcription Factor kB (NF-kB) Activation

Abstract

SUMMARY:Mutated transthyretin (TTR) fibrils are associated with the pathology of familial amyloidotic polyneuropathy (FAP), in which extracellular amyloid deposits lead to degeneration of cells and tissues, in particular neurons of the peripheral nerve. Here we present evidence that the receptor for advanced glycation end products (RAGE), previously associated with Alzheimer's disease, acts as a selective cell surface acceptor site for both soluble and fibrillar TTR. Immunohistochemical studies demonstrating increased expression of RAGE in FAP tissues suggested the relevance of this receptor to TTR-induced fibrillar pathology. In vitro studies using soluble RAGE showed saturable specific interaction with soluble and fibrillar TTR with a K d of ϳ120 nM. However, no binding was observed when soluble TTR was combined with retinol-binding protein, which represents the form in which TTR normally circulates in plasma. Specific binding of TTR to RAGE-transfected Chinese hamster ovary cells (which was completely blocked by anti-RAGE) was observed, confirming that RAGE could mediate TTR binding to cellular surfaces. RAGE-dependent activation of nuclear transcription factor kB (NF-kB) by TTR fibrils was shown in PC-12 cells stably transfected to overexpress the receptor. Furthermore, FAP nerves showed up-regulation of p50, one of the NF-kB subunits, when compared with age-matched controls. From these observations we predict that, in vivo, the presence of TTR fibrils associated with cellular surfaces of FAP patients, by contributing to NF-kB activation, leads to the pathogenesis of neurodegeneration. Further insights into the consequences of the interaction of fibrillar TTR with RAGE may therefore provide a better understanding of neurodegeneration associated with FAP. (Lab Invest 2000, 80:1101-1110.F amilial amyloidotic polyneuropathy (FAP) is a neurodegenerative disorder characterized by the extracellular deposition of transthyretin (TTR) fibrils in several tissues, particularly in the peripheral nervous system (Saraiva, 1995). In the peripheral nerves, amyloid infiltrates the epineurium, the perineurium, and especially the endoneurium. Extensive amyloid deposition is also observed in the meninges, in the spinal and autonomic ganglia, throughout the connective tissue, and in a perivascular distribution. In contrast, no amyloid deposition is detected in the brain. Mutated TTR is the main component of these amyloid fibrils. Several mutations in TTR have been described, the most common being a valine (Val) for methionine (Met) substitution at position 30 of the protein (Val30Met) (Saraiva et al, 1983). Nonmutated TTR also deposits as amyloid in senile amyloidosis (Gustavsson et al, 1995). TTR is a plasma homotetrameric protein of approximately 55 kDa produced early in development and highly conserved in evolution (Blake et al, 1974). TTR functions as a carrier for thyroxine (T 4 ) and retinol (vitamin A) (Raz et al, 1970) by formation of a complex with retinol-binding protein (RBP). Under physiological conditions, TTR circu...

Aboard transthyretin: From transport to cleavage

“…Imunohistochemical studies showing increased expression of RAGE in FAP tissues, initially suggested the relevance of this receptor to fibrillar TTR-induced pathology. In fact, the binding of aggregated TTR to RAGE was shown to trigger the activation of the transcription factor NF-kB inducing an inflammatory and apoptotic cascade of events (36). As such, it was predicted that in vivo, the association of TTR with RAGE in the cells of FAP patients would lead to neurodegeneration.…”

AGE/RAGE as a Mediator of Insulin Resistance or Metabolic Syndrome: Another Aspect of Metabolic Memory?

“…RAGE also interacts with other endogenous non-glycated peptide ligands including S100/calgranulin 56 , amphoterin (also termed as high mobility group box 1 protein, HMGB1) 57,58 , amyloid fibrills 59 , transthyretin 60 , and a leukocyte integrin, Mac-1 61 , many of which are important inflammatory regulators. Some of these inflammatory ligands for RAGE may be involved in pathogenesis of obesity and metabolic syndrome.…”

Evidence for Early Cytotoxic Aggregates in Transgenic Mice for Human Transthyretin Leu55Pro

“…9 In human FAP nerves, when cytotoxicity of nonfibrillar TTR was assessed by immunohistochemistry for inflammation and oxidative stress-associated molecules, we observed in-creased axonal expression of these markers, showing that early aggregates, in a presymptomatic phase, are toxic to cells. 8,10 This toxicity is most probably related to activation of nuclear factor (NF)-B by TTR aggregates, 11 as some inflammation-and oxidative stress-related molecules are targets of the NF-B transcription factor, 12 and activation of NF-B is found at sites of TTR deposition in FAP nerves. 11 To understand the mechanisms underlying fibril formation, deposition, and cytotoxic effects caused by aggregates, many questions remain to be investigated.…”

“…8,10 This toxicity is most probably related to activation of nuclear factor (NF)-B by TTR aggregates, 11 as some inflammation-and oxidative stress-related molecules are targets of the NF-B transcription factor, 12 and activation of NF-B is found at sites of TTR deposition in FAP nerves. 11 To understand the mechanisms underlying fibril formation, deposition, and cytotoxic effects caused by aggregates, many questions remain to be investigated. In an attempt to gain insights in the pathogenesis of FAP, several groups have generated transgenic mice carrying the human TTR Val30Met gene.…”