Fibrinogen Aα‐chain amyloidosis is a hereditary systemic amyloidosis characterized by glomerular amyloid depositions, which are derived from the fibrinogen Aα‐chain variant in humans. Despite its unique pathology, the pathogenic mechanisms of this disease are only partially understood. This is in part because comparative pathological studies on fibrinogen Aα‐chain amyloidosis are currently unavailable as there is a lack of reported cases in animals other than humans. In this study, mass spectrometry‐based proteomic analyses of Japanese squirrels (Sciurus lis) that died in five Japanese zoos showed that they developed glomerular‐associated fibrinogen Aα‐chain amyloidosis with an extremely high incidence rate (29/38 cases, 76.3%). The condition was found to be age‐dependent in the Japanese squirrels, with 89% of individuals over 4 years of age affected. Mass spectrometry revealed that the C‐terminal region of the fibrinogen Aα‐chain was involved in amyloidogenesis in Japanese squirrels as well as humans. No gene variations were identified between amyloid‐positive and amyloid‐negative squirrels, which contrasted with the available data for humans. The results indicate that fibrinogen Aα‐chain amyloidosis is a senile amyloidosis in Japanese squirrels. The results have also provided comparative pathological support that the amyloidogenic C‐terminal region of the fibrinogen Aα‐chain is involved in the characteristic glomerular pathology, regardless of the animal species. This study elucidates the potential causes of death in Japanese squirrels and will contribute to future comparative pathological studies of fibrinogen Aα‐chain amyloidosis. © 2023 The Pathological Society of Great Britain and Ireland.
