title: Accelerated amyloid deposition in mice treated with the aspartic protease inhibitor, pepstatin.
abstract: 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.
authors: Department of Medicine, Indiana University School of Medicine, Indianapolis 46202, USA.
authors: T
authors: T
authors: Yamada
authors: J
authors: J
authors: Liepnieks
authors: M D
authors: MD
authors: Benson
authors: B
authors: B
authors: Kluve-Beckerman
mesh_terms: 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*
chemical_list: 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