A mouse model of cardiac immunoglobulin light chain amyloidosis reveals insights into tissue accumulation and toxicity of amyloid fibrils
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.
Authors
- Laurent Delpy (ORCID: https://orcid.org/0000-0002-9480-8515)
- Sihem Kaaki
- Émilie Pinault (ORCID: https://orcid.org/0000-0001-8811-2661)
- Justine Pollet (ORCID: https://orcid.org/0000-0002-8670-6295)
- Pierre Sicard (ORCID: https://orcid.org/0000-0001-5837-3916)
- Alexander Carpinteiro (ORCID: https://orcid.org/0000-0002-3316-9166)
- Arnaud Jaccard (ORCID: https://orcid.org/0000-0001-7091-8253)
- Alessio Lampis (ORCID: https://orcid.org/0009-0006-3909-1386)
- Maria Victoria Ayala (ORCID: https://orcid.org/0000-0001-5164-0970)
- Vincent Javaugue (ORCID: https://orcid.org/0000-0002-1597-0283)
- Murielle Roussel (ORCID: https://orcid.org/0000-0002-4045-9428)
- Cécile Ory
- Amélie Bonaud (ORCID: https://orcid.org/0000-0002-4153-9171)
- Diana Canetti (ORCID: https://orcid.org/0000-0002-7962-7193)
- Francesca Lavatelli (ORCID: https://orcid.org/0000-0002-7693-4825)
- Eyad Naser (ORCID: https://orcid.org/0009-0008-3341-4759)
- Sébastien Bender (ORCID: https://orcid.org/0000-0002-8830-955X)
- Lia Pedroza
- Sofia Giorgetti (ORCID: https://orcid.org/0000-0001-9438-6511)
- Michael Ehrmann (ORCID: https://orcid.org/0000-0002-1927-260X)
- Alexia Rinsant
- Gemma Martinez-Rivas
- Christelle Oblet (ORCID: https://orcid.org/0000-0001-5502-7735)
- Melisa Merdanovic
- Frank Bridoux (ORCID: https://orcid.org/0000-0002-2005-8424)
- Christophe Sirac (ORCID: https://orcid.org/0000-0002-1183-4989)
- Laurence Richard
- Gilles Roussine Codo
- Weronika Karolina Swiderska
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- University of Pavia (IT)
- Université de Poitiers (FR)
- Amyloidosis Foundation (US)
- Laboratoire National de Référence (MA)
- Contrôle de la Réponse Immune B et Lymphoproliférations (FR)
- Policlinico San Matteo Fondazione (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- University College London (GB)
- University of Duisburg-Essen (DE)
- Université de Limoges (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-27
- DOI
- https://doi.org/10.1038/s41467-025-58307-2
- Citations
- 8
- Primary Topic
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Type
- article
- Field-Weighted Citation Impact
- 6.45
Funders
- Deutsche Forschungsgemeinschaft
- Agence Nationale de la Recherche
- Fondazione Cariplo
- Fondation pour la Recherche Médicale
- Fondation ARC pour la Recherche sur le Cancer
- Ligue Contre le Cancer
- Conseil Régional Aquitaine