Doxycycline Reduces Fibril Formation in a Transgenic Mouse Model of AL Amyloidosis

Abstract 1837

AL amyloidosis results from the production and aggregation of an amyloidogenic immunoglobulin (Ig) light chain (LC) by a clonal bone marrow plasma cell dyscrasia. Currently, there are no genetically reproducible animal models of AL amyloidosis. We engineered transgenic mice to express an amyloidogenic human λ6 LC. We used the cytomegalovirus (CMV) promoter to express the LC in multiple tissues and organs, circumventing the disruption of B cell development by premature expression of recombined LC in the B lineage alone. LC were detected in a number of organs including epithelial tissues of the gastrointestinal and genitourinary tracts, and in the serum. The CMV-λ6 transgenic mice developed neurologic dysfunction. By 2 years of age, >80% of the transgenic mice developed Congo-red staining human LC fibrils in the stomach. Transgenic mice were treated with the antibiotic doxycycline orally for 7 months. Of treated mice, 23% had Congophilic deposits, compared with 69% of controls drinking water for the same time period. Treatment of recombinant LC in vitro with doxycycline reduced fibril formation and the drug also caused to disruption of pre-formed fibrils, producing disordered aggregates. Thus, this transgenic model replicates the process of AL amyloidosis in vivo and is useful for testing the anti-fibril potential of orally available agents. Antibiotics such as doxycycline could prove useful in AL as well as in other amyloidoses.