Amyloid and nonfibrillar deposits in mice transgenic for wild-type human transthyretin: A possible model for senile systemic amyloidosis

The human serum protein transthyretin (TTR) is highly fibrillogenic in vitr o and is the fibril precursor in both autosomal dominant (familial amyloido tic polyneuropathy [FAP] and familial amyloidotic cardiomyopathy [FAC]) and sporadic (senile systemic amyloidosis [SSA]) forms of human cardiac amyloi dosis. We have produced mouse strains transgenic for either wild-type or mu tant (TTRLeu55Pro) human TTR genes. Eighty-four percent of C5781/6xDBA/2 mi ce older than 18 months, transgenic for the wild-type human TTR gene, devel op TTR deposits that occur primarily in heart and kidney. In most of the an imals, the deposits are nonfibrillar and non-Congophilic, but 20% of animal s older than 18 months that bear the transgene have human TTR cardiac amylo id deposits identical to the lesions seen in SSA. Amino terminal amino acid sequence analysis and mass spectrometry of the major component extracted f rom amyloid and nonamyloid deposits revealed that both were intact human TT R monomers with no evidence of proteolysis or codeposition of murine TTR. T his is the first instance in which the proteins from amyloid and nonfibrill ar deposits in the same or syngeneic animals have been shown to be identica l by sequence analysis. It is also the first time in any form of amyloidosi s that nonfibrillar deposits have been shown to systematically occur tempor ally before the appearance of fibrils derived from the same precursor in th e same tissues. These findings suggest, but do not prove, that the nonamylo id deposits represent a precursor of the fibril. The differences in the ult rastructure and binding properties of the deposits, despite the identical s izes and amino terminal amino acid sequences of the TTR and the dissociatio n of deposition and fibril formation, provide evidence that in vivo factors , perhaps associated with aging, impact on both systemic precursor depositi on and amyloid fibril formation.