Amyloid beta 42 disrupts cardiac function in Alzheimer's disease mice via SLC31A1 upregulation-mediated cuproptosis

Background Alzheimer's disease (AD) is a complex systemic disorder that extends beyond the central nervous system, exerting pathological effects on the heart. Epidemiological studies have consistently shown that individuals with AD often exhibit impaired cardiac function. While amyloid-beta (Aβ) is a key pathological hallmark of AD, primarily known for forming oligomers and fibrils in the brain, emerging evidence suggests that Aβ also exerts detrimental effects on the myocardium. Despite these observations, the precise mechanisms through which AD contributes to the onset or progression of heart failure (HF) remain poorly understood. This study aims to elucidate the underlying links between AD and HF, with a specific focus on the pathogenic role of Aβ in promoting cardiac dysfunction within experimental models of AD. Methods Cardiomyocytes and 3 × Tg-AD mouse models were used to investigate Aβ-induced cardiotoxicity and to determine the mode of myocardial cell death. We assessed cell viability, intracellular copper levels, and markers of cuproptosis. Mitochondrial oxidative respiration, ATP production, and reactive oxygen species (ROS) levels were also evaluated. Myocardial pathology and cuproptosis-related proteins were detected by histochemistry and immunoblotting. Results In 3 × Tg-AD mice, elevated cardiac Aβ paralleled cardiac dysfunction, promoted cuproptosis in cardiomyocytes, and this effect was counteracted by the copper chelator TTM which inhibited myocardial copper uptake and protected cardiac function. Building on this in vivo observation, we further investigated the mechanism in vitro and found that Aβ upregulated the copper importer SLC31A1 in vitro. Furthermore, Aβ1-42 acted synergistically with CuCl₂ or elesclomol-CuCl₂ to exacerbate cardiomyocyte death. This synergy increased intracellular copper accumulation, triggered Fe-S cluster protein loss, and promoted DLAT oligomerization-hallmarks of cuproptosis. These cuproptosis-associated changes suppressed mitochondrial oxidative respiration, decreased ATP synthesis, and elevated ROS levels. Importantly, interference with SLC31A1 expression in vivo and in vitro partially inhibited cuproptosis and protected mitochondrial or cardiac function. Conclusion Aβ1-42 disrupts copper homeostasis by upregulating SLC31A1, thereby exacerbating myocardial cuproptosis and impairing cardiac function in AD. This novel mechanism highlights SLC31A1-mediated cuproptosis as a potential therapeutic target for preserving cardiac health in AD.