# Assessment of the biochemical basis underlying the resistance against systemic amyloidosis

## TL;DR

This study explores why certain mice are resistant to a type of amyloid disease, finding that specific SAA protein variants prevent harmful amyloid structures from forming.

## Contribution

The study reveals that amyloid resistance in mice is caused by structural incompatibility of specific SAA isoforms with pathogenic fibril folds.

## Key findings

- SAA1.5 and SAA2.2 isoforms cannot form pathogenic AA amyloid fibrils under conditions where SAA1.1 does.
- Molecular dynamics simulations show that the pathogenic fibril structure is distorted by the sequences of SAA1.5 and SAA2.2.
- The resistance to amyloidosis is due to the inability of SAA1.5 and SAA2.2 to adopt the structure of harmful fibrils.

## Abstract

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.

The online version contains supplementary material available at 10.1038/s41598-026-35297-9.