Removal of Serum Amyloid A

Serum amyioid A (SAA) 1 is presumed to be the precursor for amyloid A protein, the main protein constituent found in the amyioid fibrils of reactive amyloidosis (1-3). In the mouse SAA is encoded by a family of three genes (Morrow, John F., personal communication). SAA1 and SAA2 are synthesized in the liver by hepatocytes (4-10) and are found circulating in nearly equal quantities associated with high density lipoprotein (HDL) (11). SAA3 mRNA is also expressed in the liver; however, the corresponding polypeptide has not been identified. We have found that of the three possible SAA gene products, SAA2 appears to be the sole precursor of murine amyloid fibril protein AA (12). We wish to determine by what mechanism this monotypic fibril formation occurs. One can conceive of three ways in which this could come about: (a) the gene for SAA2 could be active in tissues in which the deposits occur; (b) amyloid A fibril protein could be derived from a circulating SAA2 precursor whose concentration is selectively enhanced relative to the other SAA proteins during the induction of the disease process; and (c) there could be selective SAA~ removal from a circulating pool of possible precursors and deposition of SAA2 as amyloid A protein. We designed the experiments described here to decide among these three alternatives. To differentiate among the several possible mechanisms of amyloidosis, we searched for evidence of local SAA synthesis and examined SAA metabolism during amyloid induction at the level of SAA gene expression, synthesis, secretion, and circulatory levels. We conclude that anayloid A protein monotypy is not due to local SAA2 production, nor is it a reflection of selective increase of SAA2 isotype levels in the circulation. However, it does involve the selective and rapid removal of SAA2 from the circulating pool of both SAA~ and SAAz. Our experimental analysis clearly indicates that a combination of some feature of SAA~ interacting with itself and/or local tissue constituents is responsible for the appearance of amyloid fibrils with AA2 as the major constituent peptide.