Atrial Natriuretic Peptide Associated with Cardiovascular Diseases Inhibits Amyloid-β Aggregation via Cross-Seeding

Both cardiovascular diseases (CVDs) and Alzheimer's disease (AD) share some common risk factors (e.g., age, obesity, oxidative stress, inflammation, hypertension) that contribute to their overlapping pathogenesis, indicating a "head-to heart" pathological connection between CVDs and AD. To explore this potential connection at the protein level, we study the potential cross-seeding (heterotypic interactions) between CVDassociated atrial natriuretic peptide (ANP) and AD-associated fi- amyloid (Afi). Collective aggregation and cell assays demonstrate the cross-seeding of ANP with different Afi species including monomers, oligomers, and fibrils with high binding affinity (KD = 1.234-1.797 mu M) in a dose-dependent manner. Such ANPinduced cross-seeding also modifies the Afi aggregation pathway, fibril morphology, and cell deposition pattern by inhibiting Afi fibrillization from small aggregates, disassembling preformed Afi fibrils, and alleviating Afi-associated cytotoxicity. Finally, using transgenic C. elegans worms that express the human muscle-specific Afi1-42, ANP can also effectively delay Afi-induced worm paralysis, decrease Afi plaques in worm brains, and reduce reactive oxygen species (ROS) production, confirming its in vivo inhibition ability to prevent neurodevelopmental toxicity in worms. This work discovers not only a new cross-seeding system between the two disease-related proteins but also a new finding that ANP possesses a new biological function as an Afi inhibitor in the nonaggregated state.