• Mélanie Bézard, Amira Zaroui, Mounira Kharoubi, France Lam, Elsa Poullot, Emmanuel Teiger, Onnik Agbulut, Thibaud Damy, and Ekaterini Kordeli.
• Sorbonne Université, Institut de Biologie Paris-Seine (IBPS), UMR CNRS 8256, INSERM U1164, Biological Adaptation and Ageing, Paris-France.
• Amyloid. 2024 Sep 1; 31 (3): 209219209-219.

BackgroundCardiac involvement in systemic light chain amyloidosis (AL) leads to chronic heart failure and is a major prognosis factor. Severe cellular defects are provoked in cardiac cells by tissue-deposited amyloid fibrils of misfolded free immunoglobulin light chains (LCs) and their prefibrillar oligomeric precursors.ObjectiveUnderstanding the molecular mechanisms behind cardiac cell cytotoxicity is necessary to progress in therapy and to improve patient management. One key question is how extracellularly deposited molecules exert their toxic action inside cardiac cells. Here we searched for direct evidence of amyloid LC uptake by cardiomyocytes in patient biopsies.MethodsWe immunolocalized LCs in cardiac biopsies from four AL cardiac amyloidosis patients and analysed histopathological images by high resolution confocal microscopy and 3D image reconstruction.ResultsWe show, for the first time directly in patient tissue, the presence of LCs inside cardiomyocytes, and report their proximity to nuclei and to caveolin-3-rich areas. Our observations point to macropinocytosis as a probable mechanism of LC uptake.ConclusionsInternalisation of LCs occurs in patient cardiomyocytes. This event could have important consequences for the pathogenesis of the cardiac disease by enabling interactions between amyloid molecules and cellular organelles inducing specific signalling pathways, and might bring new insight regarding treatment.

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