Amyloid formation in the rat: adenoviral expression of mouse serum amyloidA proteins

Serum amyloid A (SAA) proteins are acute-phase apolipoproteins that are ass ociated with high-density lipoprotein (HDL) particles. SAA proteins are pre cursors to secondary amyloid fibril proteins and under certain conditions o f 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 s how amyloid deposition. In the rat, a deletion in the SAA1/SAA2 gene is ass ociated with the absence of protein in the plasma and subsequently no amylo id deposition is detected. We have generated adenoviral vectors to study th e expression of SAA proteins on HDL metabolism avid amyloid formation. Inje ction of SAA viruses into rats resulted in expression of the mouse SAA prot eins in the plasma with specific association of the SAA with HDL particles. The induction of SAA proteins was comparable to that seen in mice presente d with the inflammatory agent, bacterial lipopolysaccharide (LPS). Adenovir al induced SAA levels were maintained for up to several weeks without a sig nificant 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, l iver, 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 amy loidogenic SAA protein. Furthermore, the expression of the adenoviral SAA p rotein from the liver and incorporation onto HDL particles further supports the hypothesis that AA amyloid is derived from circulating SAA protein. Th e ease of use of the adenoviral vectors and the rat provide an excellent mo del to study the function of SAA proteins.