AA amyloidosis belongs to the class of systemic amyloidosis which involves the deposition of misfolded proteins in multiple organs. The resulting aggregated structures, called amyloid fibrils, cause organ failure and disruption. Despite the incidence of the disease has decreased concurrently with the reduction of Tuberculosis cases in Western countries, there is still a considerable prevalence of the pathology in some patients with chronic inflammation. Indeed, individuals suffering from Type II Diabetes and Rheumatoid Arthritis can develop AA Amyloidosis. Our main interest involves AA amyloidosis in cats, proposing them as models for the pathology. Our recent study revealed a high prevalence of the disease in cats living in shelters (Ferri et al., PLoS One. 2023, doi: 10.1371/journal.pone.0281822). A similar pattern was observed by Zhang et al. in cheetahs living in captivity, suggesting the existence of horizontal transmission.

Serum Amyloid A (SAA) is the major protein involved in the disease, and it most commonly aggregates in kidneys, liver, and spleen. SAA production increases during the acute inflammatory phase and it’s involved in the lipid transport and clearance of inflammation sites. However, the molecular mechanisms of SAA aggregation and amyloidogenesis are still to be defined. With the help of Cryo-Electron Microscopy (or Cryo-EM), we conduct multiorgan studies to determine the structure of AA fibrils extracted ex-vivo from affected cats. Our recent work showed the structure of an AA amyloid from the kidney of a diseased cat. We suggested that an eight-residue insert in the cat SAA sequence causes an increased stability of the amyloid core (Schulte et al., Nat Commun. 2022, doi: 10.1038/s41467-022-34743-2). Thanks to the structural studies coupled with biophysical and biochemical analyses, we aim to decipher the mysteries of AA amyloid formation and bring additional knowledge to the field of amyloidogenic diseases to develop efficient drugs.

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