Disruption of the transthyretin gene results in mice with depressed levels of plasma retinol and thyroid hormone.

Episkopou, Vasso; Maeda, Shuichiro; Nishiguchi, Seiji; Shimada, Kazunori; Gaitanaris, George A.; Gottesman, Max E.; Robertson, Elizabeth J.

doi:10.1073/pnas.90.6.2375

Cited by 293 publications

(243 citation statements)

References 43 publications

(39 reference statements)

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“…APP23 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 targeted disruption (6)(7)(8).…”

Section: Resultsmentioning

confidence: 99%

Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of Aβ toxicity

Buxbaum¹,

Ye²,

Reixach³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

261

251

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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...

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Section: Resultsmentioning

confidence: 99%

Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of Aβ toxicity

Buxbaum¹,

Ye²,

Reixach³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

261

251

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“…The RBP-TTR complex is proposed to be the physiological circulatory retinol transport complex of humans and other terrestrial vertebrates (Vieira et al, 1995). The elimination of the normal RBP-TTR complex, as occurs in the TTR-null mouse model (Episkopou et al, 1993), or by treatment with fenretinide (Berni and Formelli, 1992), results in a significant reduction in plasma RBP and consequently retinol. Despite low plasma levels of retinol (Ͻ6% normal) the embryos of TTR-null mice develop normally and have similar viability and fertility to mice carrying the normal TTR gene (Wei et al, 1995).…”

Section: Transthyretin and Retinol-binding Protein Interactionmentioning

confidence: 99%

Evolution of the Thyroid Hormone-Binding Protein, Transthyretin

Power

Elias

Richardson

et al. 2000

General and Comparative Endocrinology

190

119

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Transthyretin (TTR) belongs to a group of proteins, which includes thyroxine-binding globulin and albumin, that bind to and transport thyroid hormones in the blood. TTR is also indirectly implicated in the carriage of vitamin A through the mediation of retinol-binding protein (RBP). It was first identified in 1942 in human serum and cerebrospinal fluid and was formerly called prealbumin for its ability to migrate faster than serum albumin on electrophoresis of whole plasma. It is a single polypeptide chain of 127 amino acids (14,000 Da) and is present in the plasma as a tetramer of noncovalently bound monomers. The major sites of synthesis of TTR in eutherian mammals, marsupials, and birds are the liver and choroid plexus but in reptiles it is synthesised only in the choroid plexus. The observation that TTR is strongly expressed in the choroid plexus but not in the liver of the stumpy-tailed lizard and the strong conservation of expression in the choroid plexus from reptiles to mammals have been taken as evidence to suggest that extrahepatic synthesis of TTR evolved first. The identification and cloning of TTR from the liver of an amphibian, Rana catesbeiana, and a teleost fish, Sparus aurata, and its absence from the choroid plexus of both species suggest an alternative model for its evolution. Protein modelling studies are presented that demonstrate differences in the electrostatic characteristics of the molecule in human, rat, chicken, and fish, which may explain why, in contrast to TTR from human and rat, TTR from fish and birds preferentially binds triiodo-L-thyronine.

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“…Mice used in this study included TTR-null mice 22 and Tg mice carrying the human TTR V30M gene backcrossed to the TTR-null background. 20 Animals were kept and used strictly in accordance with National and European Union guidelines for the care and handling of laboratory animals.…”

Section: Animalsmentioning

confidence: 99%

Immunization in familial amyloidotic polyneuropathy: counteracting deposition by immunization with a Y78F TTR mutant

Terazaki

Ando

Fernandes

et al. 2006

Laboratory Investigation

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The mechanism of amyloid formation in familial amyloidotic polyneuropathy (FAP), a hereditary disorder associated with mutant transthyretin (TTR), is still unknown. It is generally believed that altered conformations exposing cryptic regions are intermediary steps in this mechanism. A TTR mutant-Y78F (transthyretin mutant with phenylalanine replacing tyrosine at position 78)-designed to destabilize the native structure has been shown to expose a cryptic epitope recognized by a monoclonal antibody that reacts only with highly amyloidogenic mutants presenting the amyloid fold or with amyloid fibrils. To test whether TTR deposition in FAP can be counteracted by antibodies for cryptic epitopes, we immunized with TTR Y78F, transgenic mice carrying the most common FAP-associated TTR mutant-V30M (transthyretin mutant with methionine replacing valine at position 30)-at selected ages that present normally with either nonfibrillar or TTR amyloid deposition. Compared to age-matched control nonimmunized mice, Y78F-immunized mice had a significant reduction in TTR deposition usually found in this strain, in particular in stomach and intestine; by contrast, animals immunized with V30M did not show differences in deposition in comparison with nonimmunized mice. Immunohistochemical analyses of tissues revealed that immunization with Y78F lead to infiltration by lymphocytes and macrophages at common deposition sites, but not in tissues such as liver, choroid plexus, and Langerhans islets, in which TTR is produced. These results suggest that Y78F induced production of an antibody that reacts specifically with deposits and leads to an immune response effective in removing/ preventing TTR deposition. Therefore, TTR immunization with selected TTR mutants has potential application in immune therapy for FAP.

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Disruption of the transthyretin gene results in mice with depressed levels of plasma retinol and thyroid hormone.

Abstract: Transthyretin (

Cited by 293 publications

References 43 publications

Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of Aβ toxicity

Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of Aβ toxicity

Evolution of the Thyroid Hormone-Binding Protein, Transthyretin

Immunization in familial amyloidotic polyneuropathy: counteracting deposition by immunization with a Y78F TTR mutant

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