Amyloid formation in the rat: Adenoviral expression of mouse serum amyloid A proteins

Abstract

Serum amyloid A (SAA) proteins are acute-phase apolipoproteins that are associated with high-density lipoprotein (HDL) particles: SAA proteins are precursors to secondary amyloid fibril proteins and under certain conditions of chronic or recurrent inflammation these proteins are deposited as amyloid fibrils. Of two isotypes found in mouse, SAA1.1 and SAA2.1, only SAA1.1 is deposited into amyloid. The CE/J mouse is unique, in that the only isoform identified is a hybrid between SAA1.1 and SAA2.1 and the mouse does not show amyloid deposition. In the rat, a deletion in the SAA1/SAA2 gene is associated with the absence of protein in the plasma and subsequently no amyloid deposition is detected. We have generated adenoviral vectors to study the expression of SAA proteins on HDL metabolism and amyloid formation. Injection of SAA viruses into rats resulted in expression of the mouse SAA proteins in the plasma with specific association of the SAA with HDL particles. The induction of SAA proteins was comparable to that seen in mice presented with the inflammatory agent, bacterial lipopolysaccharide (LPS). Adenoviral induced SAA levels were maintained for up to several weeks without a significant decrease in SAA expression. Injection of rats with the mouse SAA1.1 adenoviral vector, followed by amyloid enhancing factor (AEF) and silver nitrate resulted in the deposition of amyloid fibrils in the spleen. After 2 weeks, amyloid could be detected in other tissues, including the heart, liver, kidneys and lungs. When animals were injected with null or the SAA2.2 virus no amyloid was detected. These studies demonstrate that the inability of the rat to develop AA amyloid is due to the lack of synthesizing an amyloidogenic SAA protein. Furthermore, the expression of the adenoviral SAA protein from the liver and incorporation onto HDL particles further supports the hypothesis that AA amyloid is derived from circulating SAA protein. The ease of use of the adenoviral vectors and the rat provide an excellent model to study the function of SAA proteins.

Proliferative and Nonproliferative Lesions of the Rat and Mouse Urinary System

“…Type A fibrils are the major component in experimental animals (Röchen and Shakespeare 2002). The protein precursor of amyloid is SAA, a family of major acute-phase proteins produced by the liver under the influence of cytokines (Yu et al 2000). The acute phase protein under normal circumstances is degraded, however in mouse, hamster and man this protein can be deposited as amyloid in the kidney with extensive alterations in the glomeruli, tubules and interstitium.…”

A Concise Review of Amyloidosis in Animals

“…The duck genome contained a single copy of the SAA gene that was expressed in the liver and lungs of ducklings, even in the absence of induction of acute phase response [22]. Amyloid-resistant mouse strains were found to have a non-amyloidogenic acute phase SAA [45, 46], and rats were shown not to form acute phase SAA and AA-amyloid at all [47, 48]. Additionally, there are other animal species that appear to be prone to amyloid deposition.…”

Serum amyloid A-dependent inflammasome activation and acute injury in a mouse model of experimental stroke

“…Adenoviral preparation. The production of replication defective adenoviral vectors expressing mouse SAA proteins has been described using second generation adenoviral vector 76,77 . Briefly, Recombinant adenoviruses were expanded in 293 human embryonic kidney (HEK) cells.…”