Pathogenetic mechanisms of amyloid A amyloidosis

Abstract

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.

Hepatic Expression of Serum Amyloid A1 Is Induced by Traumatic Brain Injury and Modulated by Telmisartan

“…This rapid and pronounced elevation of SAA1 monomers could lead to formation of amyloidogenic oligomers and further high molecular weight aggregates, as were shown for SAA amyloidosis. 52 To detect the SAA1 amyloid species, we used a recently developed approach 53 where aggregates are detected after enrichment on the basis of their detergent resistance and high molecular weight. This procedure was previously used to detect polyglutamine amyloid aggregates from cells, as well as amyloid aggregates from yeast cells.…”

Amyloid and inflammation

“…The precursor of AA is serum amyloid A (SAA), an HDL-associated apolipoprotein. In PNAS, Simons et al mine a unique transgenic model for AA amyloidosis to consider the role of inflammation in defining this form of amyloid in the mouse (5).…”

“…Export of SAA from the liver can be abrogated by colchicine, providing a mechanism for treatment and prevention of AA amyloid. Simons et al use a doubletransgenic model in which both a doxycycline-inducible SAA2 transgene and a liverspecific reverse tet transactivator transgene are inserted, achieving peak SAA2 levels of 2-5 mg/dL and higher (5). This result is remarkable in the sustained levels of SAA attained, and with regard to the insertion of multiple copies of a specific amyloidogenic SAA isoform bypassing cytokine induction.…”

“…The double-transgenic model and the authors' considerable experience with in vivo imaging of amyloid deposits have allowed Simons et al to address the kinetics of SAA/AA interconversion with regard to the latency of deposition, priming, and regression induced by reducing the precursor or immunological clearance (3,5). Probes for determining the in vivo amyloid load, and for monitoring treatment, include SAP, anti-AA antibodies, and HPSG ligands, in each instance controlling for possible cross-reactivity with circulating and soluble precursors in normal tissue and contiguous to fibrillar deposits (3,5,16,17).…”

“…Probes for determining the in vivo amyloid load, and for monitoring treatment, include SAP, anti-AA antibodies, and HPSG ligands, in each instance controlling for possible cross-reactivity with circulating and soluble precursors in normal tissue and contiguous to fibrillar deposits (3,5,16,17). Studies carried out during SAA triggering by inflammatory stimuli and amyloid induction have shown an ∼90-min half-life and a large HDL APR SAA pool as a result of increased hepatic synthesis, only 0.01% of which is deposited in the mouse spleen over a 24-h period (18).…”