Specific pathogen free conditions prevent transthyretin amyloidosis in mouse models

Inoue, Seiya; Ohta, Mika; Li, Zhenghua; Zhao, Gang; Takaoka, Yutaka; Sakashita, Naomi; Miyakawa, Kazuhisa; Takada, Koji; Tei, Hajime; Suzuki, Misao; Masuoka, Michio; Sakaki, Yoshiyuki; Takahashi, Kiyoshi; Yamamura, Ken Ichi

doi:10.1007/s11248-008-9180-9

Cited by 14 publications

(13 citation statements)

References 38 publications

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“…The role of environment had to be addressed when these transgenics were moved from a conventional animal facility to a specific pathogen free facility. With that move the mice stopped developing tissue deposits to the same extent as previously [52]. As expected they showed a difference in the gastrointestinal flora in the two locales and hypothesized that some degree of inflammation was required to stimulate the formation of tissue aggregates [53].…”

Section: Murine Models Of the Human Amyloidosessupporting

confidence: 62%

Animal models of human amyloidoses: Are transgenic mice worth the time and trouble?

Buxbaum

2009

FEBS Letters

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Edited by Per HammarströmKeywords: Amyloidosis Transgenic model Amyloid A AL amyloid Cystatin c Gelsolin Transthyretin Alzheimer's disease Serpinopathies Familial dementias a b s t r a c tThe amyloidoses are the prototype gain of toxic function protein misfolding diseases. As such, several naturally occurring animal models and their inducible variants provided some of the first insights into these disorders of protein aggregation. With greater analytic knowledge and the increasing flexibility of transgenic and gene knockout technology, new models have been generated allowing the interrogation of phenomena that have not been approachable in more reductionist systems, i.e. behavioral readouts in the neurodegenerative diseases, interactions among organ systems in the transthyretin amyloidoses and taking pre-clinical therapeutic trials beyond cell culture. The current review describes the features of both transgenic and non-transgenic models and discusses issues that appear to be unresolved even when viewed in their organismal context.

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Section: Murine Models Of the Human Amyloidosessupporting

confidence: 62%

Animal models of human amyloidoses: Are transgenic mice worth the time and trouble?

Buxbaum

2009

FEBS Letters

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“…However, amyloid deposition in the heart and kidney was not found, even at 24 months of age, in these lines under the conventional conditions used in this study ( Table 1). In general, there was less amyloid deposition in this experiment than that previously reported [15,39].…”

Section: Onset and Degree Of Amyloid Fibril Depositioncontrasting

confidence: 50%

“…We previously reported that amyloid deposition was observed in the heart and kidney of the +/+:Tg and −/−:Tg lines [15,35]. However, this result was not reproduced in this experiment, perhaps because of different housing conditions, as amyloid deposition is greatly affected by environmental conditions [39]. The amount of amyloid deposits differs under various conventional conditions [44].…”

Section: Discussionmentioning

confidence: 59%

Amyloid deposition in a mouse model humanized at the transthyretin and retinol-binding protein 4 loci

Lyu

Shen

et al. 2018

Laboratory Investigation

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Familial amyloidotic polyneuropathy is an autosomal dominant disorder caused by a point mutation in the transthyretin (TTR) gene. The process of TTR amyloidogenesis begins with rate-limiting dissociation of the TTR tetramer. Thus, the TTR stabilizers, such as Tafamidis and Diflunisal, are now in clinical trials. Mouse models will be useful to testing the efficacy of these drugs. Although several mouse models have been generated, they all express mouse Rbp4. Thus, human TTR associates with mouse RBP4, resulting in different kinetic and thermodynamic stability profiles of TTR tetramers. To overcome this problem, we previously produced humanized mouse strains at both the TTR and Rbp4 loci (Ttr , Ttr , and Rbp4 ). By mating these mice, we produced double-humanized mouse strains, Ttr :Rbp4 and Ttr :Rbp4 . We used conventional transgenic mouse strains on a wild-type (Ttr :Tg[6.0hTTRMet30]) or knockout Ttr background (Ttr:Tg[6.0hTTRMet30]) as reference strains. The double-humanized mouse showed 1/25 of serum hTTR and 1/40 of serum hRBP4 levels. However, amyloid deposition was more pronounced in Ttr :Rbp4 than in conventional transgenic mouse strains. In addition, a similar amount of amyloid deposition was also observed in Ttr :Rbp4 mice that carried the wild-type human TTR gene. Furthermore, amyloid deposition was first observed in the sciatic nerve without any additional genetic change. In all strains, anti-TTR antibody-positive deposits were found in earlier age and at higher percentage than amyloid fibril deposition. In double-humanized mice, gel filtration analysis of serum revealed that most hTTR was free of hRBP4, suggesting importance of free TTR for amyloid deposition.

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“…Studies on the influence of environmental factors in kidney amyloidosis are contradictory. Renal deposits in transgenic mice expressing the human TTR gene were absent in specific pathogen-free conditions (19) but persisted in other experimental evaluations under the same environment (20).…”

Section: Epidemiology and Geneticsmentioning

confidence: 93%

Transthyretin Amyloidosis and the Kidney

Lobato

Rocha

2012

Clinical Journal of the American Society of Nephrology

121

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SummaryThe amyloidoses are protein-misfolding disorders associated with progressive organ dysfunction. Immunoglobulin light chain is the most common, amyloid A the longest recognized, and transthyretin-associated amyloidosis (ATTR) the most frequent inherited systemic form. Although ATTR, an autosomal-dominant disease, is associated with at least 100 different transthyretin (TTR) mutations, the single amino-acid substitution of methionine for valine at position 30 is the most common mutation. Each variant has a different organ involvement, although clinical differences attributed to environmental and genetic factors exist within the same mutation. Peripheral neuropathy and cardiomyopathy are broadly described, and insights into disease reveal that kidney impairment and proteinuria are also clinical features. This review combines clinical and laboratory findings of renal involvement from the main geographic regions of disease occurrence and for different mutations of TTR. Fifteen nephropathic variants have been described, but the TTR V30M mutation is the best documented. Nephropathy affects patients with late-onset neuropathy, low penetrance in the family, and cardiac dysrhythmias. Microalbuminuria can be the disorder's first presentation, even before the onset of neuropathy. Amyloid renal deposits commonly occur, even in the absence of urinary abnormalities. The experience with renal replacement therapy is based on hemodialysis, which is associated with poor survival. Because TTR is synthesized mainly in the liver, liver transplantation has been considered an acceptable treatment; simultaneous liver-kidney transplantation is recommended to avoid recurrence of nephropathy. In addition, the kidney-safety profile of new drugs in development may soon be available.

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Specific pathogen free conditions prevent transthyretin amyloidosis in mouse models

Cited by 14 publications

References 38 publications

Animal models of human amyloidoses: Are transgenic mice worth the time and trouble?

Animal models of human amyloidoses: Are transgenic mice worth the time and trouble?

Amyloid deposition in a mouse model humanized at the transthyretin and retinol-binding protein 4 loci

Transthyretin Amyloidosis and the Kidney

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