Abstract
AA-amyloidosis is a disease characterized by abnormal deposition of serum A amyloid (SAA) peptide along with other components in various organs. The disease is a complication of inflammatory conditions that cause persistent high levels of the acute phase reactant SAA in plasma. In experimental animal models, the deposited amyloid is resolved when the inflammation is stopped, suggesting that there is an efficient clearance mechanism for the amyloid. As heparan sulfate (HS) is one of the major components in the amyloid, its metabolism is expected to affect the pathology of AA amyloidosis. In this study, we investigated the effect of heparanase, a HS degradation enzyme, in resolution of the AA amyloid. The transgenic mice deficient in heparanase (Hpa-KO) produced a similar level of SAA in plasma as the wildtype control (Ctr) mice upon induction by injection of AEF (amyloid enhancing factor) and inflammatory stimuli. The induction resulted in formation of SAA amyloid 7-days post treatment in the spleen that displayed a comparable degree of amyloid load in both groups. The amyloid became significantly less in the Hpa-KO spleen than in the Ctr spleen 10-days post treatment, and was completely resolved in the Hpa-KO spleen on day 21 post induction, while a substantial amount was still detected in the Ctr spleen. The rapid clearance of the amyloid in the Hpa-KO mice can be ascribed to upregulated matrix metalloproteases (MMPs) that are believed to contribute to degradation of the protein components in the AA amyloid. The results indicate that both heparanase and MMPs play important parts in the pathological process of AA amyloidosis.
Highlights
Amyloidosis is a heterogeneous group of diseases characterized by extracellular deposition of abnormal proteins in the form of fibrils
To induce AA amyloidosis, mice, C57bl/6 (Ctr) and heparanase-knockout (Hpa-KO), at the age of 12 weeks were injected with 100 mg of amyloid enhancing factor (AEF) into the tail vein, followed by subcutaneous injection of 0.2 ml of 1% silver nitrate to stimulate inflammation
Accumulated information ratifies that heparan sulfate (HS) is essential for AA amyloidosis [8,10]
Summary
Amyloidosis is a heterogeneous group of diseases characterized by extracellular deposition of abnormal proteins in the form of fibrils. More than 20 proteins are identified to be able to form amyloid, including serum A amyloid protein (SAA). This apoliprotein is an acute phase reactant associated with highdensity lipoprotein (HDL). The SAA level returns to the basal level after inflammation is stopped; a persist high plasma level of SAA in the circumstance of chronic inflammation may lead to aggregation of the protein, by a yet unknown mechanism, subsequently leading to abnormal deposition of the protein in organs such as the spleen, liver and kidney [2]. The disease is rare, but often severe with high mortality due to functional failure of affected organs
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
