Assessment of the biochemical basis underlying the resistance against systemic amyloidosis

Amyloid resistance is the reduced or abrogated ability of an organism to develop a specific type of amyloid disease. For example, it was found that certain mouse strains show resistance against systemic AA amyloidosis, due to mutations in the amyloid fibril precursor protein serum amyloid A (SAA). In this research, we find that the SAA1.5 and 2.2, two SAA-isoforms that underlie amyloid resistance in mice are unable to adopt the structure of pathogenic AA amyloid fibrils under conditions, where the pathogenic protein variant SAA1.1 does so. Furthermore, molecular dynamics simulations show that the pathogenic fibril structure does not tolerate the sequential changes present in SAA1.5 and 2.2 and becomes distorted by the variant sequences. These data imply that SAA1.5 and SAA2.2 cause amyloid resistance due to a structural incompatibility of their sequences with the specific fold of pathogenic AA amyloid fibrils.