Expression of mouse apolipoprotein SAA1.1 in CE/J mice: isoform-specific effects on amyloidogenesis.
Amyloid A (AA) amyloid deposition in mice is dependent upon isoform-specific effects of the serum amyloid A (SAA) protein. In type A mice, SAA1.1 and SAA2.1 are the major apolipoprotein-SAA isoforms found on high-density lipoproteins. During inflammation, both isoforms are increased 1000-fold, but only SAA1.1 is selectively deposited into amyloid fibrils. Previous studies showed that the CE/J mouse strain is resistant to amyloid induction. This resistance is not due to a deficiency in SAA synthesis, but is probably related to the unusual SAA isoform present. The CE/J mouse has a single acute-phase SAA protein (SAA2.2), which is a composite of the SAA1.1 and SAA2.1, with an amino terminus similar to the nonamyloidogenic SAA2.1. Recently, genetic experiments suggested that the SAA2.2 isoform might provide protection from amyloid deposition. To determine the amyloidogenic potential of the CE/J mouse, we generated SAA adenoviral vectors to express the various isoforms in vitro and in vivo. Purified recombinant SAA proteins demonstrated that SAA1.1 was fibrillogenic in vitro, whereas SAA2.2 was unable to form fibrils. Incubation of increasing concentrations of the nonamyloidogenic SAA2.2 protein with the amyloidogenic SAA1.1 did not inhibit the fibrillogenic nature of SAA1.1, or alter its ability to form extensive fibrils. Injection of the mouse SAA1.1 or SAA2.2 adenoviral vectors into mice resulted in isoform-specific expression of the SAA proteins. Amyloid induction after viral expression of the SAA1.1 protein resulted in the deposition of amyloid fibrils in the CE/J mouse, whereas SAA2.2 expression had no effect. Similar expression of the SAA2.2 protein in C57BL/6 mice did not alter amyloid deposition. These data demonstrate that the failure of the CE/J mouse to deposit amyloid is due to the structural inability of the SAA2.2 to form amyloid fibrils. This mouse provides a unique system to test the amyloidogenic potential of altered SAA proteins and to determine the important structural features of the protein.
Yu
J
J
Department of Biochemistry, University of Kentucky, Lexington, USA.
Zhu
H
H
Guo
J T
JT
de Beer
F C
FC
Kindy
M S
MS
D000256:Adenoviridae; D000595:Amino Acid Sequence; D000682:Amyloid / Q000032:analysis / Q000096:biosynthesis; D000818:Animals; D001053:Apolipoproteins / Q000737:chemistry / Q000235:genetics*; D005822:Genetic Vectors; D007249:Inflammation / Q000503:physiopathology; D008075:Lipoproteins, HDL / Q000097:blood; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D000685:Serum Amyloid A Protein / Q000737:chemistry
D000682:Amyloid; D001053:Apolipoproteins; D008075:Lipoproteins, HDL; D020033:Protein Isoforms; C489995:Saa2 protein, mouse; D000685:Serum Amyloid A Protein; C035165:apolipoprotein SAA