Amyloid and nonfibrillar deposits in mice transgenic for wild-type human transthyretin: A possible model for senile systemic amyloidosis

Mei Hui Teng, Jian Yun Yin, Ruben Vidal, Jorge Ghiso, Asok Kumar, Rahmin Rabenou, Alan Shah, Daniel R. Jacobson, Clement E. Tagoe, Gloria Gallo, Joel Buxbaum

Research output: Contribution to journalArticle

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Abstract

The human serum protein transthyretin (TTR) is highly fibrillogenic in vitro and is the fibril precursor in both autosomal dominant (familial amyloidotic polyneuropathy [FAP] and familial amyloidotic cardiomyopathy [FAC]) and sporadic (senile systemic amyloidosis [SSA]) forms of human cardiac amyloidosis. We have produced mouse strains transgenic for either wild-type or mutant (TTRLeu55Pro) human TTR genes. Eighty-four percent of C57Bl/6xDBA/2 mice older than 18 months, transgenic for the wild-type human TTR gene, develop TTR deposits that occur primarily in heart and kidney. In most of the animals, the deposits are nonfibrillar and non-Congophilic, but 20% of animals older than 18 months that bear the transgene have human TTR cardiac amyloid deposits identical to the lesions seen in SSA. Amino terminal amino acid sequence analysis and mass spectrometry of the major component extracted from amyloid and nonamyloid deposits revealed that both were intact human TTR monomers with no evidence of proteolysis or codeposition of murine TTR. This is the first instance in which the proteins from amyloid and nonfibrillar deposits in the same or syngeneic animals have been shown to be identical by sequence analysis. It is also the first time in any form of amyloidosis that nonfibrillar deposits have been shown to systematically occur temporally before the appearance of fibrils derived from the same precursor in the same tissues. These findings suggest, but do not prove, that the nonamyloid deposits represent a precursor of the fibril. The differences in the ultrastructure and binding properties of the deposits, despite the identical sizes and amino terminal amino acid sequences of the TTR and the dissociation of deposition and fibril formation, provide evidence that in vivo factors, perhaps associated with aging, impact on both systemic precursor deposition and amyloid fibril formation.

Original languageEnglish (US)
Pages (from-to)385-396
Number of pages12
JournalLaboratory Investigation
Volume81
Issue number3
StatePublished - 2001
Externally publishedYes

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Prealbumin
Amyloid Plaques
Amyloidosis
Transgenic Mice
Polyneuropathies
Protein Sequence Analysis
Transgenes
Cardiomyopathies
Amyloid
Proteolysis
Genes
Sequence Analysis
Blood Proteins
Amino Acid Sequence
Mass Spectrometry
Kidney

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Teng, M. H., Yin, J. Y., Vidal, R., Ghiso, J., Kumar, A., Rabenou, R., ... Buxbaum, J. (2001). Amyloid and nonfibrillar deposits in mice transgenic for wild-type human transthyretin: A possible model for senile systemic amyloidosis. Laboratory Investigation, 81(3), 385-396.

Amyloid and nonfibrillar deposits in mice transgenic for wild-type human transthyretin : A possible model for senile systemic amyloidosis. / Teng, Mei Hui; Yin, Jian Yun; Vidal, Ruben; Ghiso, Jorge; Kumar, Asok; Rabenou, Rahmin; Shah, Alan; Jacobson, Daniel R.; Tagoe, Clement E.; Gallo, Gloria; Buxbaum, Joel.

In: Laboratory Investigation, Vol. 81, No. 3, 2001, p. 385-396.

Research output: Contribution to journalArticle

Teng, MH, Yin, JY, Vidal, R, Ghiso, J, Kumar, A, Rabenou, R, Shah, A, Jacobson, DR, Tagoe, CE, Gallo, G & Buxbaum, J 2001, 'Amyloid and nonfibrillar deposits in mice transgenic for wild-type human transthyretin: A possible model for senile systemic amyloidosis', Laboratory Investigation, vol. 81, no. 3, pp. 385-396.
Teng, Mei Hui ; Yin, Jian Yun ; Vidal, Ruben ; Ghiso, Jorge ; Kumar, Asok ; Rabenou, Rahmin ; Shah, Alan ; Jacobson, Daniel R. ; Tagoe, Clement E. ; Gallo, Gloria ; Buxbaum, Joel. / Amyloid and nonfibrillar deposits in mice transgenic for wild-type human transthyretin : A possible model for senile systemic amyloidosis. In: Laboratory Investigation. 2001 ; Vol. 81, No. 3. pp. 385-396.
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abstract = "The human serum protein transthyretin (TTR) is highly fibrillogenic in vitro and is the fibril precursor in both autosomal dominant (familial amyloidotic polyneuropathy [FAP] and familial amyloidotic cardiomyopathy [FAC]) and sporadic (senile systemic amyloidosis [SSA]) forms of human cardiac amyloidosis. We have produced mouse strains transgenic for either wild-type or mutant (TTRLeu55Pro) human TTR genes. Eighty-four percent of C57Bl/6xDBA/2 mice older than 18 months, transgenic for the wild-type human TTR gene, develop TTR deposits that occur primarily in heart and kidney. In most of the animals, the deposits are nonfibrillar and non-Congophilic, but 20{\%} of animals older than 18 months that bear the transgene have human TTR cardiac amyloid deposits identical to the lesions seen in SSA. Amino terminal amino acid sequence analysis and mass spectrometry of the major component extracted from amyloid and nonamyloid deposits revealed that both were intact human TTR monomers with no evidence of proteolysis or codeposition of murine TTR. This is the first instance in which the proteins from amyloid and nonfibrillar deposits in the same or syngeneic animals have been shown to be identical by sequence analysis. It is also the first time in any form of amyloidosis that nonfibrillar deposits have been shown to systematically occur temporally before the appearance of fibrils derived from the same precursor in the same tissues. These findings suggest, but do not prove, that the nonamyloid deposits represent a precursor of the fibril. The differences in the ultrastructure and binding properties of the deposits, despite the identical sizes and amino terminal amino acid sequences of the TTR and the dissociation of deposition and fibril formation, provide evidence that in vivo factors, perhaps associated with aging, impact on both systemic precursor deposition and amyloid fibril formation.",
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AU - Yin, Jian Yun

AU - Vidal, Ruben

AU - Ghiso, Jorge

AU - Kumar, Asok

AU - Rabenou, Rahmin

AU - Shah, Alan

AU - Jacobson, Daniel R.

AU - Tagoe, Clement E.

AU - Gallo, Gloria

AU - Buxbaum, Joel

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