Pulmonary vascular amyloidosis in aged dogs. A new form of spontaneously occurring amyloidosis derived from apolipoprotein AI

Abstract

The N-terminus of a mutant form of apolipoprotein AI [apoAI] has previously been shown to be the subunit protein of amyloid fibrils in a human kindred with a form of familial amyloid polyneuropathy (FAP, type III) and in a recently reported kindred with a form of non-neuropathic hereditary amyloidosis. In this study, we demonstrate by amino-acid sequence analysis, that a form of vascular amyloidosis occurring in the lungs of aged dogs is derived from a N-terminal fragment of apoAI and that no amino acid substitution is present in this confirmed sequence. This represents the first documentation of apoAI as a precursor for a form of amyloidosis in animals, and provides the first documentation of apoAI as a precursor for amyloid fibrils in a form of age-associated ("senile") amyloidosis. Secondary structure prediction analysis of the N-terminal regions of normal human and dog apoAI indicated a propensity for beta-pleated sheet conformation, and thus amyloidogenesis, in 40 and 45% of the respective sequences. These results suggest that apoAI (like transthyretin) may serve as an amyloid precursor protein for both familial and senile forms of amyloidosis. ApoAI should, therefore, be considered as a potential amyloid precursor when forms of human senile amyloidosis of unknown origin are evaluated.