Journal Article

A mouse model of cardiac immunoglobulin light chain amyloidosis reveals insights into tissue accumulation and toxicity of amyloid fibrils

Martinez-Rivas, Gemma, Bender, Sebastien, Merdanovic, Melisa, Lampis, Alessio, Pedroza, Laura, Canetti, Diana, Giorgetti, Sofia, Lavatelli, Francesca, Ehrmann, Michael, Naser, Eyad, Pollet, Justine, Jaccard, Arnaud, Kaaki, Sihem, Delpy, Laurent, Sicard, Pierre, Rinsant, Alexa, Bridoux, Frank, Carpinteiro, Alexander, Javaugue, Vincent, Ory, Cécile, Swiderska, Weronika Karolina, Richard, Laurence, Oblet, Christelle, Roussel, Muriel, Codo, Gilles Roussine, Ayala, Maria Victoria, Sirac, Christophe, Bonaud, Amélie, Pinault, Emilie

2025

Overview

Immunoglobulin light chain (LC) amyloidosis (AL) is one of the most common types of systemic amyloidosis but there is no reliable in vivo model for better understanding this disease. Here, we develop a transgenic mouse model producing a human AL LC. We show that the soluble full length LC is not toxic but a single injection of pre-formed amyloid fibrils or an unstable fragment of the LC leads to systemic amyloid deposits associated with early cardiac dysfunction. AL fibrils in mice are highly similar to that of human, arguing for a conserved mechanism of amyloid fibrils formation. Overall, this transgenic mice closely reproduces human cardiac AL amyloidosis and shows that a partial degradation of the LC is likely to initiate the formation of amyloid fibrils in vivo, which in turn leads to cardiac dysfunction. This is a valuable model for research on AL amyloidosis and preclinical evaluation of new therapies. The pathophysiology of Amyloid light-chain (AL) amyloidosis remains poorly understood due to the lack of reliable in vivo models. Here, the authors describe a transgenic mouse model that reproduces cardiac AL amyloidosis and provides new information on the formation of AL amyloid fibrils.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/109 / 13/31 / 14 / 14/19 / 14/28 / 14/3 / 14/34 / 38 / 38/91 / 42 / 45 / 45/23 / 45/41 / 49 / 59 / 631/1647/334/1874/345 / 631/337/470/2284 / 64 / 64/110 / 692/699/1541 / 82/16 / 82/29 / 82/51 / 82/58 / 82/83 / 9/25 / 96 / Amyloid / Amyloid - metabolism / Amyloid - toxicity / Amyloidosis / Amyloidosis - metabolism / Amyloidosis - pathology / Animal models / Animals / Bioaccumulation / Biocompatibility / Cardiology and cardiovascular system / Disease Models, Animal / Endocrinology and metabolism / Fibrillogenesis / Human health and pathology / Humanities and Social Sciences / Humans / Immunoglobulin Light Chains - genetics / Immunoglobulin Light Chains - metabolism / Immunoglobulin Light-chain Amyloidosis - genetics / Immunoglobulin Light-chain Amyloidosis - metabolism / Immunoglobulin Light-chain Amyloidosis - pathology / Immunoglobulins / Life Sciences / Male / Mice / Mice, Transgenic / multidisciplinary / Myocardium - metabolism / Myocardium - pathology / Science / Science (multidisciplinary) / Toxicity / Transgenic mice