Accelerated amyloid deposition in mice treated with the aspartic protease inhibitor, pepstatin.
The development of amyloidotic diseases is believed to be determined in large part by the structure and metabolism of the amyloid subunit protein. The amino-terminal region of serum amyloid A (SAA), the subunit precursor protein in reactive amyloidosis, appears to confer fibrillogenic potential. Here we present data consistent with the hypothesis that amyloid A fibrillogenesis is favored when proteolysis of the amino-terminal region of SAA is impaired. Murine tissue extracts were found to contain pepstatin-inhibitable protease activity that cleaved mouse SAA2 between Glu8 and Ala9. Tissues obtained from mice that had been treated with pepstatin for 3 days lacked this activity. To investigate a possible relationship between inhibition of aspartic proteases and amyloidogenesis, mice were treated with pepstatin while concurrently undergoing a standard amyloid induction protocol (repeated casein injections). Pepstatin-treated mice showed amyloid deposition significantly sooner than the control group, which had received only casein. During the preamyloidotic phase, pepstatin-treated mice had higher concentrations of SAA in serum and spleen than control mice. In addition, clearance of injected 125I-labeled SAA from plasma was significantly delayed. Based on these findings, it is reasonable to postulate that inhibition of aspartic protease activity can lead to an accumulation of amino-terminally intact SAA molecules and thereby accelerate amyloid fibril formation.
Yamada
T
T
Department of Medicine, Indiana University School of Medicine, Indianapolis 46202, USA.
Liepnieks
J
J
Benson
M D
MD
Kluve-Beckerman
B
B
D000818:Animals; D001053:Apolipoproteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D007150:Immunohistochemistry; D008099:Liver / Q000737:chemistry; D051379:Mice; D008808:Mice, Inbred CBA; D010436:Pepstatins / Q000494:pharmacology*; D011498:Protein Precursors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000276:immunology*
D001053:Apolipoproteins; D010436:Pepstatins; D011498:Protein Precursors; D012333:RNA, Messenger; D000685:Serum Amyloid A Protein; C014195:Streptomyces pepsin inhibitor; D016282:Aspartic Acid Endopeptidases; C031375:pepstatin