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.
Elliott-Bryant
R
R
Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA 01730, USA.
Liang
J S
JS
Sipe
J D
JD
Cathcart
E S
ES
D000595:Amino Acid Sequence; D000818:Animals; D001053:Apolipoproteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D050356:Lipid Metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D051379:Mice; D008808:Mice, Inbred CBA; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D011994:Recombinant Proteins / Q000378:metabolism; D013154:Spleen / Q000166:cytology
D001053:Apolipoproteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; C035165:apolipoprotein SAA