apo‐SAA1/apo‐SAA2 Isotype Ratios during Casein‐ and Amyloid‐Enhancing‐Factor‐Induced Secondary Amyloidosis in A/J and C57BL/6J Mice

Hebert, Lise; Gervais, Francine

doi:10.1111/j.1365-3083.1990.tb02756.x

Cited by 15 publications

(10 citation statements)

References 37 publications

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“…As WT mice with chronic inflammation become amyloidotic, the SAA1:SAA2 concentration ratio increases sharply, and the total circulating SAA value falls modestly, consistent with selective sequestration of SAA2 into amyloid (32,33). Our present finding of a dramatic fall of SAA2 values in all of the transgenic mice as amyloid was being deposited was similarly consistent with such sequestration.…”

Section: Discussionsupporting

confidence: 77%

Pathogenetic mechanisms of amyloid A amyloidosis

Simons

Al‐Shawi

Ellmerich

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Systemic amyloid A (AA) amyloidosis is a serious complication of chronic inflammation. Serum AA protein (SAA), an acute phase plasma protein, is deposited extracellularly as insoluble amyloid fibrils that damage tissue structure and function. Clinical AA amyloidosis is typically preceded by many years of active inflammation before presenting, most commonly with renal involvement. Using dose-dependent, doxycycline-inducible transgenic expression of SAA in mice, we show that AA amyloid deposition can occur independently of inflammation and that the time before amyloid deposition is determined by the circulating SAA concentration. High level SAA expression induced amyloidosis in all mice after a short, slightly variable delay. SAA was rapidly incorporated into amyloid, acutely reducing circulating SAA concentrations by up to 90%. Prolonged modest SAA overexpression occasionally produced amyloidosis after long delays and primed most mice for explosive amyloidosis when SAA production subsequently increased. Endogenous priming and bulk amyloid deposition are thus separable events, each sensitive to plasma SAA concentration. Amyloid deposits slowly regressed with restoration of normal SAA production after doxycycline withdrawal. Reinduction of SAA overproduction revealed that, following amyloid regression, all mice were primed, especially for rapid glomerular amyloid deposition leading to renal failure, closely resembling the rapid onset of renal failure in clinical AA amyloidosis following acute exacerbation of inflammation. Clinical AA amyloidosis rarely involves the heart, but amyloidotic SAA transgenic mice consistently had minor cardiac amyloid deposits, enabling us to extend to the heart the demonstrable efficacy of our unique antibody therapy for elimination of visceral amyloid.

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Section: Discussionsupporting

confidence: 77%

Pathogenetic mechanisms of amyloid A amyloidosis

Simons

Al‐Shawi

Ellmerich

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Furthermore, our AEF-treated control group showed no differences from the PBS-treated control mice (group 1) with respect to any of the APR studied (data not shown), indicating that AEF per se is non-inflammatory and that the induction of the acute phase response in our experiments was due solely to AgN03 administration. This is in agreement with other reports that AEF does not induce an acute inflammatory response [25,26]. + rmIL-lra (W) (as described in Table 1).…”

Section: Resultssupporting

confidence: 94%

Down‐regulation of the major circulating precursors of proteins deposited in secondary amyloidosis by a recombinant mouse interleukin‐1 receptor antagonist

1997

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An inflammatory response was induced in C57BL/6 mice using silver nitrate. Co-administration of a recombinant mouse interleukin-1 receptor antagonist (rmIL-1ra) significantly reduced the magnitude of hepatic induction of the mRNA specifying the serum amyloid A (A-SAA) isoforms A-SAA1 and A-SAA2 for up to 24 h. In relative terms, the amount by which the induction of serum A-SAA protein levels could be countered by the antagonist was less, probably reflecting extrahepatic A-SAA synthesis that is regulated independently of IL-1. Induction of hepatic serum amyloid P component (SAP) mRNA and other acute-phase reactant (APR) mRNA were all partially blocked by rmIL-1ra for up to 24 h, indicating that induction of these APR mRNA involves both IL-1 and additional factors acting independently of IL-1. Hepatic mRNA levels of the negative APR apolipoprotein A-I (apo A-I) and serum albumin were down-regulated by silver nitrate treatment; rmIL-1ra partially restored serum albumin mRNA levels but not those of apo A-I. The IL-1ra-mediated reduction in inflammation-induced hepatic mRNA and serum protein concentrations of A-SAA and SAP (the precursors of the main protein components of amyloid deposits in secondary amyloidosis) was, however, not sufficient to prevent or delay early amyloid deposition in the silver nitrate/amyloid enhancing factor model of accelerated amyloidosis. The rmIL-1ra may be a useful component in future therapies to control inflammation and secondary amyloidosis; in addition, it will be a useful tool for the detailed analysis of the IL-1-driven aspects of inflammation per se.

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“…Some evidence for SAA deposition in tissues of amyloidotie mice was demonstrated in several earlier studies. First, it was found that during amyloid deposition the level of apo SAA2 (one of two SAA isomers) was decreased in the serum of amyloidotie mice without a corresponding reduction in hepatic SAAi mRNA level [31,32]. Since no detectable synthesis of SAA was found in spleen and there was amino acid sequence identity between apo SAA; and protein AA [33], It was suggested that SAA2 is selectively removed from circulation, deposited in tissues and then it degraded to protein AA [31].…”

Section: Discussionmentioning

confidence: 99%

Direct Evidence for SAA Deposition in Tissues During Murine Amyloidogenesis

et al. 1994

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To study the mechanism of amyloid deposition, the nature of amyloid proteins formed in experimental murine amyloidosis, was examined. Spleen specimens, 15-60 mg, were homogenized and extracted using aqueous acidic acetonitrile, in a recently developed procedure, making it possible to obtain amyloid proteins from minute amounts of tissue. The extracted material, 1.5-4 mg, was analysed by Western blotting and ELISA using antibodies recognizing differentially proteins AA and SAA. Two immunoreactive proteins of 8 and 12 KDa were isolated and subjected to amino acid analysis and N-terminal sequence determination. The results of immunochemical and chemical examination showed that the 8 and 12 KDa proteins represented proteins AA and SAA, respectively. The data obtained provide new direct evidence for SAA in tissues during murine amyloidogenesis.

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apo‐SAA1/apo‐SAA2 Isotype Ratios during Casein‐ and Amyloid‐Enhancing‐Factor‐Induced Secondary Amyloidosis in A/J and C57BL/6J Mice

Cited by 15 publications

References 37 publications

Pathogenetic mechanisms of amyloid A amyloidosis

Pathogenetic mechanisms of amyloid A amyloidosis

Down‐regulation of the major circulating precursors of proteins deposited in secondary amyloidosis by a recombinant mouse interleukin‐1 receptor antagonist

Direct Evidence for SAA Deposition in Tissues During Murine Amyloidogenesis

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