Catabolism of Lipid‐Free Recombinant Apolipoprotein Serum Amyloid A by Mouse Macrophages In Vitro Results in Removal of the Amyloid Fibril‐Forming Amino Terminus

Serum amyloid A fibrils are formed when the normally rapid catabolism of the acute‐phase reactant apolipoprotein serum amyloid A (apoSAA) is incomplete; thus amyloidosis may be viewed as a condition of dysregulated proteolysis. There is evidence that apoSAA is dissociated from plasma high‐density lipoprotein (HDL) prior to fibril formation. The objective of this study was to investigate degradation of lipid‐free apoSAA by tissue macrophages derived from amyloid‐susceptible CBA/J mice in vitro. Peritoneal macrophages derived from untreated (normal) mice converted apoSAA (12 kDa) to a single 4 kDa C‐terminal peptide while splenic macrophages converted apoSAA to 10, 7 and 4 kDa C‐terminal peptides and a 4 kDa peptide that lacked the C‐ and N‐terminal regions. Similar patterns of proteolysis occurred when peritoneal and splenic macrophages from amyloidotic CBA/J mice were used. Conditioned medium prepared from peritoneal, but not splenic macrophages, degraded apoSAA. Specific sites of cleavage indicated activity of cathepsin G‐ and elastase‐like neutral proteases. The data indicate that lipid‐free apoSAA can be degraded by secreted or cell‐associated neutral proteases that are generated by macrophages to yield peptides that lack fibrillogenic potential.