Cells that have evolved to produce large quantities of secreted proteins to serve the integrated functions of complex multicellular organisms are equipped to compensate for protein misfolding. Hepatocytes and plasma cells have well developed chaperone and proteasome systems to ensure that secreted proteins transit the cell efficiently. The number of neurodegenerative disorders associated with protein misfolding suggests that neurons are particularly sensitive to the pathogenic effects of aggregates of misfolded molecules because those systems are less well developed in this lineage. Aggregates of the amyloidogenic (A␤ 1-42) peptide play a major role in the pathogenesis of Alzheimer's disease (AD), although the precise mechanism is unclear. In genetic studies examining protein-protein interactions that could constitute native mechanisms of neuroprotection in vivo, overexpression of a WT human transthyretin (TTR) transgene was ameliorative in the APP23 transgenic murine model of human AD. Targeted silencing of the endogenous TTR gene accelerated the development of the neuropathologic phenotype. Intraneuronal TTR was seen in the brains of normal humans and mice and in AD patients and APP23 mice. The APP23 brains showed colocalization of extracellular TTR with A␤ in plaques. Using surface plasmon resonance we obtained in vitro evidence of direct protein-protein interaction between TTR and A␤ aggregates. These findings suggest that TTR is protective because of its capacity to bind toxic or pretoxic A␤ aggregates in both the intracellular and extracellular environment in a chaperone-like manner. The interaction may represent a unique normal host defense mechanism, enhancement of which could be therapeutically useful.protein interaction ͉ protein misfolding ͉ amyloidosis ͉ dementia A relationship between Alzheimer's disease (AD) and transthyretin (TTR) has been hypothesized on the basis of reports of physical interaction between amyloidogenic (A␤) peptides and TTR proteins in vitro, prevention of A␤ aggregation in Caenorhabditis elegans transgenic for both mutant A␤ and TTR, increased cerebral transcription of the TTR gene in murine AD models, immunohistochemically detectable TTR in the vicinity of A␤ plaques in A␤ transgenic mice, and more aggressive histologic disease in such mice after local treatment with anti-TTR antibody (1-5). However, none of those studies demonstrated functional effects of the putative TTR-A␤ interaction. We performed genetic experiments designed to determine whether TTR has an effect on the development of the neuropathologic and behavioral phenotypes in a well characterized murine model of human AD. ResultsAPP23 mice, carrying the Swedish autosomal dominant AD mutation and displaying the neuropathologic (Congophilic plaques, gliosis, neuronal death, Congophilic angiopathy) and behavioral (defined cognitive deficits) features associated with human AD, were mated with mice overexpressing WT human TTR (hTTR) and animals in which both copies of the endogenous TTR gene had been silenced by targete...

Transthyretin (TTR) is a 55 kD homotetrameric serum protein transporter of retinol binding protein charged with retinol and thyroxine (T4). The highly amyloidogenic human TTR variant in which leucine at position 55 is replaced by proline (L55P TTR) is responsible for aggressive fatal amyloidosis with peripheral and autonomic neuropathy, cardiomyopathy and nephropathy. Mice bearing one or two copies of a 19.2 kB human genomic fragment containing the entire coding sequence and the known control regions of the L55P TTR transgene, failed to develop TTR amyloidosis even though their sera contained mutant human TTR. The frequency of TTR tissue deposition was increased when the L55P TTR transgene was bred onto a murine TTR-null background. Denaturation of sera from the transgenic animals and murine TTR-knockouts expressing the human L55P TTR transgene revealed that the TTR tetramer was much more stable in the presence of the murine protein because the TTR circulates as hybrid human/murine heterotetramers. Intraperitoneal administration of diflunisal, a non-steroidal anti-inflammatory drug that binds to TTR in its T4-binding site and inhibits fibril formation in vitro, to human L55P TTR transgenic animals in which the murine TTR gene had been silenced, also stabilizes the circulating mutant protein to in vitro urea denaturation.