Antisense oligonucleotide suppression of serum amyloid A reduces amyloid deposition in mice with AA amyloidosis

Amyloid A (AA) amyloidosis is a condition in which amyloid fibrils characterized by a linear morphology and a cross-β structure accumulate and are deposited extracellularly in organs, resulting in chronic inflammatory diseases and infections. The incidence of AA amyloidosis is high in humans and several animal species. Serum amyloid A (SAA) is one of the most important precursor amyloid proteins and plays a vital step in AA amyloidosis. Amyloid enhancing factor (AEF) serves as a seed for fibril formation and shortens the onset of AA amyloidosis sharply. In this study, we examined whether AEFs extracted and purified from five animal species (camel, cat, cattle, goat, and mouse) could promote mouse SAA (mSAA) protein aggregation in vitro using quantum-dot (QD) nanoprobes to visualize the aggregation. The results showed that AEFs shortened and promoted mSAA aggregation. In addition, mouse and cat AEFs showed higher mSAA aggregation-promoting activity than the camel, cattle, and goat AEFs. Interestingly, homology analysis of SAA in these five animal species revealed a more similar amino acid sequence homology between mouse and cat than between other animal species. Furthermore, a detailed comparison of amino acid sequences suggested that it was important to mSAA aggregation-promoting activity that the 48th amino acid was a basic residue (Lys) and the 125th amino acid was an acidic residue (Asp or Glu). These data imply that AA amyloidosis exhibits higher transmission activity among animals carrying genetically homologous SAA gene, and may provide a new understanding of the pathogenesis of amyloidosis.

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Serum amyloid A forms stable oligomers that disrupt vesicles at lysosomal pH and contribute to the pathogenesis of reactive amyloidosis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1707120114 ◽

2017 ◽

Vol 114 (32) ◽

pp. E6507-E6515 ◽

Cited By ~ 29

Author(s):

Shobini Jayaraman ◽

Donald L. Gantz ◽

Christian Haupt ◽

Olga Gursky

Keyword(s):

Serum Amyloid A ◽

Major Complication ◽

Lipid Vesicles ◽

Serum Amyloid ◽

High Density Lipoproteins ◽

Aa Amyloidosis ◽

Intrinsically Disordered ◽

Amyloid A ◽

Α Helix ◽

Structural Methods

Serum amyloid A (SAA) is an acute-phase plasma protein that functions in innate immunity and lipid homeostasis. SAA is a protein precursor of reactive AA amyloidosis, the major complication of chronic inflammation and one of the most common human systemic amyloid diseases worldwide. Most circulating SAA is protected from proteolysis and misfolding by binding to plasma high-density lipoproteins. However, unbound soluble SAA is intrinsically disordered and is either rapidly degraded or forms amyloid in a lysosome-initiated process. Although acidic pH promotes amyloid fibril formation by this and many other proteins, the molecular underpinnings are unclear. We used an array of spectroscopic, biochemical, and structural methods to uncover that at pH 3.5–4.5, murine SAA1 forms stable soluble oligomers that are maximally folded at pH 4.3 with ∼35% α-helix and are unusually resistant to proteolysis. In solution, these oligomers neither readily convert into mature fibrils nor bind lipid surfaces via their amphipathic α-helices in a manner typical of apolipoproteins. Rather, these oligomers undergo an α-helix to β-sheet conversion catalyzed by lipid vesicles and disrupt these vesicles, suggesting a membranolytic potential. Our results provide an explanation for the lysosomal origin of AA amyloidosis. They suggest that high structural stability and resistance to proteolysis of SAA oligomers at pH 3.5–4.5 help them escape lysosomal degradation, promote SAA accumulation in lysosomes, and ultimately damage cellular membranes and liberate intracellular amyloid. We posit that these soluble prefibrillar oligomers provide a missing link in our understanding of the development of AA amyloidosis.

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Amyloid deposition in granuloma of tuberculosis patients: A pilot study

10.1101/2021.02.08.21250526 ◽

2021 ◽

Author(s):

Shreya Ghosh ◽

Akansha Garg ◽

Chayanika Kala ◽

Ashwani Kumar Thakur

Keyword(s):

Serum Amyloid A ◽

Amyloid Deposition ◽

Serum Amyloid ◽

Secondary Amyloidosis ◽

Amyloid Formation ◽

Tuberculosis Patients ◽

Amyloid A ◽

Inflammatory Conditions ◽

Amyloid Deposits ◽

Serum Amyloid A Protein

AbstractThe formation of granuloma is one of the characteristic feature of tuberculosis. Besides, rise in the concentration of acute phase response proteins mainly serum amyloid A is the indicator for chronic inflammation associated with tuberculosis. Serum amyloid A drives secondary amyloidosis in tuberculosis and other chronic inflammatory conditions. The linkage between serum amyloid A (SAA) protein and amyloid deposition site is not well understood in tuberculosis and other chronic inflammatory conditions. We hypothesized that granuloma could be a potential site for amyloid deposition because of the presence of serum amyloid A protein and proteases that cleave SAA and trigger amyloid formation. Based on this hypothesis, for the first time we have shown the presence of amyloid deposits in the granuloma of tuberculosis patients using the gold standard, Congo red dye staining.

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Effect of etanercept on serum amyloid A protein (SAA) levels in patients with AA amyloidosis complicating inflammatory arthritis

Clinical Rheumatology ◽

10.1007/s10067-008-0875-3 ◽

2008 ◽

Vol 27 (7) ◽

pp. 923-925 ◽

Cited By ~ 19

Author(s):

M. E. Perry ◽

Anne Stirling ◽

J. A. Hunter

Keyword(s):

Inflammatory Arthritis ◽

Serum Amyloid A ◽

Serum Amyloid ◽

Aa Amyloidosis ◽

Amyloid A ◽

Serum Amyloid A Protein

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Serum Amyloid A and AA Amyloidosis

Protein Misfolding, Aggregation, and Conformational Diseases - Protein Reviews ◽

10.1007/978-0-387-36534-3_12 ◽

2007 ◽

pp. 241-256

Author(s):

Zafer Ali-Khan

Keyword(s):

Serum Amyloid A ◽

Serum Amyloid ◽

Aa Amyloidosis ◽

Amyloid A

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Abdominal Fat Aspiration Biopsy and Genotyping of Serum Amyloid A Contribute to Early Diagnosis of Reactive AA Amyloidosis Secondary to Rheumatoid Arthritis

Internal Medicine ◽

10.2169/internalmedicine.42.800 ◽

2003 ◽

Vol 42 (9) ◽

pp. 800-805 ◽

Cited By ~ 12

Author(s):

Watara ISHII ◽

Masayuki MATSUDA ◽

Akinori NAKAMURA ◽

Naoshi NAKAMURA ◽

Akio SUZUKI ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Early Diagnosis ◽

Serum Amyloid A ◽

Abdominal Fat ◽

Serum Amyloid ◽

Aspiration Biopsy ◽

Aa Amyloidosis ◽

Amyloid A

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Typing of Amyloidosis in Renal Biopsies: Diagnostic Pitfalls

Archives of Pathology & Laboratory Medicine ◽

10.5858/2007-131-917-toairb ◽

2007 ◽

Vol 131 (6) ◽

pp. 917-922 ◽

Cited By ~ 3

Author(s):

Anjali A. Satoskar ◽

Kelly Burdge ◽

Daniel J. Cowden ◽

Gyongyi M. Nadasdy ◽

Lee A. Hebert ◽

...

Keyword(s):

Light Chain ◽

Serum Amyloid A ◽

Serum Amyloid ◽

Immunofluorescence Staining ◽

Moderate Intensity ◽

Light Chains ◽

Aa Amyloidosis ◽

Amyloid A ◽

Renal Biopsies ◽

Diagnostic Pitfalls

Abstract Context.—Amyloidosis represents a group of diseases with extracellular deposition of congophilic fibrils of similar morphology but differing chemical composition. The types commonly involving the kidney are AL (light chain amyloid) and AA (serum amyloid A). Familial amyloidosis can also affect the kidney, but we have not encountered such a case during the study period. Distinguishing between the AL and AA forms of amyloid is clinically important because of the different treatments and outcomes. The classification of amyloidosis is made by immunostaining with antibodies to κ and λ immunoglobulin light chains and for serum amyloid A protein. Objective.—To draw attention to the nonspecific immunofluorescence staining patterns in renal biopsies with amyloidosis, causing potential diagnostic pitfalls. Design.—Renal biopsies from 15 patients, including 13 cases of AL and 2 cases of AA amyloidosis, were studied. Immunofluorescence staining with routine antibody panel and immunoperoxidase staining for amyloid A were performed. Results.—Of the 13 cases of AL amyloidosis, 2 cases showed little difference in staining intensity between κ and λ light chains (2+ and 3+, respectively) and 4 cases showed only moderate intensity (2+) of the predominant light chain. The 2 cases diagnosed as AA amyloidosis also exhibited staining for light chains. One case had strong (3+) signal for κ and moderate (2+) for λ light chain, while the other showed weaker staining. Conclusions.—Immunofluorescence staining for immunoglobin light chains on renal biopsy, as the first step to differentiate between AL and AA amyloidosis, may sometimes be inconclusive or even misleading. Applying amyloid A immunostain on a routine basis and detailed clinical history are essential to avoid misclassification.

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