A transgenic mouse model reproduces human hereditary systemic amyloidosis

Michèle Chabert, Xavier Rousset, Magali Colombat, Michel Lacasa, Hermine Kakanakou, Mathilde Bourderioux, Pierre Brousset, Odile Burlet-Schiltz, Juris J. Liepnieks, Barbara Kluve-Beckerman, Gilles Lambert, François P. Châtelet, Merrill Benson, Athina D. Kalopissis

Research output: Contribution to journalArticle

Abstract

Amyloidoses are rare life-threatening diseases caused by protein misfolding of normally soluble proteins. The fatal outcome is predominantly due to renal failure and/or cardiac dysfunction. Because amyloid fibrils formed by all amyloidogenic proteins share structural similarity, amyloidoses may be studied in transgenic models expressing any amyloidogenic protein. Here we generated transgenic mice expressing an amyloidogenic variant of human apolipoprotein AII, a major protein of high density lipoprotein. According to amyloid nomenclature this variant was termed STOP78SERApoAII. STOP78SER-APOA2 expression at the physiological level spontaneously induced systemic amyloidosis in all mice with full-length mature STOP78SER-ApoAII identified as the amyloidogenic protein. Amyloid deposits stained with Congo red were extracellular, and consisted of fibrils of approximately 10 nm diameter. Renal glomerular amyloidosis was a major feature with onset of renal insufficiency occurring in mice older than six months of age. The liver, heart and spleen were also greatly affected. Expression of STOP78SER-APOA2 in the liver and intestine in mice of the K line but not in other amyloid-laden organs showed they present systemic amyloidosis. The amyloid burden was a function of STOP78SER-APOA2 expression and age of the mice with amyloid deposition starting in two-month-old high-expressing mice that died from six months onwards. Because STOP78SER-ApoAII conserved adequate lipid binding capacity as shown by high STOP78SER-ApoAII amounts in high density lipoprotein of young mice, its decrease in circulation with age suggests preferential deposition into preformed fibrils. Thus, our mouse model faithfully reproduces early-onset hereditary systemic amyloidosis and is ideally suited to devise and test novel therapies.

Original languageEnglish (US)
JournalKidney international
DOIs
StatePublished - Jan 1 2019

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Familial Amyloidosis
Transgenic Mice
Amyloidosis
Amyloid
Amyloidogenic Proteins
HDL Lipoproteins
Renal Insufficiency
Proteostasis Deficiencies
Apolipoprotein A-II
Congo Red
Fatal Outcome
Liver
Amyloid Plaques
Terminology
Intestines
Proteins
Spleen
Kidney
Lipids

Keywords

  • glomerular amyloid deposits
  • hereditary systemic amyloidosis
  • mouse model

ASJC Scopus subject areas

  • Nephrology

Cite this

Chabert, M., Rousset, X., Colombat, M., Lacasa, M., Kakanakou, H., Bourderioux, M., ... Kalopissis, A. D. (2019). A transgenic mouse model reproduces human hereditary systemic amyloidosis. Kidney international. https://doi.org/10.1016/j.kint.2019.03.013

A transgenic mouse model reproduces human hereditary systemic amyloidosis. / Chabert, Michèle; Rousset, Xavier; Colombat, Magali; Lacasa, Michel; Kakanakou, Hermine; Bourderioux, Mathilde; Brousset, Pierre; Burlet-Schiltz, Odile; Liepnieks, Juris J.; Kluve-Beckerman, Barbara; Lambert, Gilles; Châtelet, François P.; Benson, Merrill; Kalopissis, Athina D.

In: Kidney international, 01.01.2019.

Research output: Contribution to journalArticle

Chabert, M, Rousset, X, Colombat, M, Lacasa, M, Kakanakou, H, Bourderioux, M, Brousset, P, Burlet-Schiltz, O, Liepnieks, JJ, Kluve-Beckerman, B, Lambert, G, Châtelet, FP, Benson, M & Kalopissis, AD 2019, 'A transgenic mouse model reproduces human hereditary systemic amyloidosis', Kidney international. https://doi.org/10.1016/j.kint.2019.03.013
Chabert M, Rousset X, Colombat M, Lacasa M, Kakanakou H, Bourderioux M et al. A transgenic mouse model reproduces human hereditary systemic amyloidosis. Kidney international. 2019 Jan 1. https://doi.org/10.1016/j.kint.2019.03.013
Chabert, Michèle ; Rousset, Xavier ; Colombat, Magali ; Lacasa, Michel ; Kakanakou, Hermine ; Bourderioux, Mathilde ; Brousset, Pierre ; Burlet-Schiltz, Odile ; Liepnieks, Juris J. ; Kluve-Beckerman, Barbara ; Lambert, Gilles ; Châtelet, François P. ; Benson, Merrill ; Kalopissis, Athina D. / A transgenic mouse model reproduces human hereditary systemic amyloidosis. In: Kidney international. 2019.
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