Cathepsin D activity protects against development of type AA amyloid fibrils.
BACKGROUND
The extracellular, fibrillar deposits of reactive (secondary) amyloidosis are composed of amyloid A (AA) protein, a proteolytically derived fragment of the acute phase protein serum amyloid A (SAA). While complete degradation of SAA precludes amyloid formation, limited cleavage which generates AA protein is considered part of the pathogenic mechanism.


METHODS
In this study, we investigated SAA degradation by lysosomal enzymes cathepsins B, D, and K, and assessed the impact of cathepsin activity on AA amyloid formation in a cell culture model using peripheral blood mononuclear cells from healthy volunteers.


RESULTS
Lysates of human mononuclear cells were capable of degrading SAA. Degradation was significantly reduced by inhibition of cathepsin D with pepstatin A. Inhibition of cathepsin B or cathepsin K, however, had no effect. The SAA fragment pattern generated by mononuclear cell lysates was similar to that produced by incubating SAA with purified human cathepsin D. Consistent with in vitro findings, amyloid formation in human monocyte cultures was increased by 43% when cathepsin D was inhibited, but remained unaffected by inhibition of cathepsin B or cathepsin K.


CONCLUSIONS
These data provide evidence that cathepsin D but not cathepsin B or cathepsin K is physiologically important in SAA degradation and hence in preventing SAA from accumulating and serving as precursor of AA amyloid fibrils.
van der Hilst
J C H
JC
Department of General Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. j.vanderhilst@aig.umcn.nl
Kluve-Beckerman
B
B
van der Meer
J W M
JW
Simon
A
A
D000682:Amyloid / Q000378:metabolism*; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D002402:Cathepsin D / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D000685:Serum Amyloid A Protein / Q000378:metabolism*
D000682:Amyloid; D000685:Serum Amyloid A Protein; D002403:Cathepsins; D002401:Cathepsin B; C534130:CTSK protein, human; D056657:Cathepsin K; D002402:Cathepsin D