From protective enzyme to facilitator of amyloid propagation: Cathepsin D-mediated amyloid fibril fragmentation

Amyloid fibrils, linked to severe pathologies such as neurodegenerative diseases, pose a significant challenge to modern medicine. Lysosomal proteases, particularly cathepsins, have attracted attention for their potential role in modulating amyloid pathologies, especially in the context of immunotherapy. However, the impact of these proteases on mature amyloids remains poorly understood. This study investigates the effects of cathepsin D (CTSD), a lysosomal aspartyl protease, on mature amyloid fibrils associated with local insulin and systemic lysozyme amyloidoses, as well as neurodegenerative Alzheimer's and Parkinson's diseases. Our results demonstrate that CTSD induces fragmentation of all examined fibril types, presumably by disrupting hydrogen bonds between the beta-strands forming the fibril backbone. This fragmentation occurs without depolymerizing or destructuring the amyloids and does not reduce their toxic effects on immortalized and primary cell lines. Furthermore, the size, structure, and properties of CTSD-induced amyloid degradation products suggest that the enzyme may contribute to the rapid accumulation and propagation of pathological amyloids at both intercellular and tissue levels in mammals. This finding is valuable for understanding physiological processes and developing immunotherapeutic strategies, as artificially stimulating the immune response may exacerbate pathological conditions.