Abstract
Most studies of experimental amyloid A protein (AA) amyloidosis in mice have been performed in type A mice with BALB/c as the prototype. In these mice the products of two genes, SAA1 and SAA2, are the major apo-SAA isoforms on high density lipoprotein (HDL). Of these two isoforms, that differ at nine amino acids, only apo-SAA2 is rapidly cleared and deposited as amyloid fibrils. No mouse strain has ever been shown to be completely resistant to amyloid induction. We have found the CE/J mouse strain to be exceedingly resistant to amyloidogenesis. Data indicate that this resistance is not due to a lack of apo-SAA synthesis but rather resides in the unique apo-SAA isoform in this strain. CE/J mice have a single major apo-SAA isoform (pI 6.15) the product of a single gene. This is a hybrid molecule with features of both apo-SAA1 and apo-SAA2, differing from the latter at only six amino acids. When CD studies were performed to explore the structural relationship of this isoform to apo-SAA1 and apo-SAA2, we found that when bound to heparan sulfate proteoglycan the CE/J pI 6.15 isoform fails to undergo the beta-sheet folding typical for apo-SAA2. This evidence suggests that the folding effect of heparan sulfate proteoglycan on apo-SAA2 is important in amyloid formation.
Highlights
Affairs Medical Center, kxington, Kentucky 40536 and the ¶Department of Biochemistry, MedicalResearch Council Groupin Protein Structure andFunction, university of Alberta, Edmonton TBG2H7, Canada
Data indicate that this resistance of already assembled fibrils [11].Additional evidence linking is not due to a lack of apo-Serum amyloid A protein (SAA) synthesis but rather HSPG to amyloidogenesis comes from animal studies that resides in the unique apo-SAA isoform in this strain. show its coincidental deposition with amyloid A protein (AA) protein regardless
Expression of an amyloidogenic human transthyretin in a transgenicmouse model resulted in its deposition as amyloid [14]. These diverse precursors have an inherent amyloidogenicity that even cross species.We suggest that HSPGcould play a mechanistic role in fibrillogenesis by interacting with this putative structural motif of amyloid proteins resulting in /3-sheet folding of the precursor
Summary
Affairs Medical Center, kxington, Kentucky 40536 and the ¶Department of Biochemistry, MedicalResearch Council Groupin Protein Structure andFunction, university of Alberta, Edmonton TBG2H7, Canada. HDL apo-SAAconstitutes 35 and 21% of the total apolipoproteins of LPS-injected CE/Jand BALB/c mice, respectively (Fig1.,lunes 2 and 3).This was determined by pyridine extraction of Coomassie-stained gels [30]. 6.15) and thequantitatively minor apo-SAAs. Similar results were obtained when mice were injectedwith casein (data not SAA isoforms (Fig.2).
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