Fibrilization in mouse senile amyloidosis is fibril conformation-dependent

Amyloidosis refers to a group of diseases characterized by tissue depositio n of amyloid fibrils. A single intravenous injection of a very small amount of the native mouse senile amyloid fibrils (AApoAII) induced severe system ic amyloid deposition in young mice having the amyloidogenic apoA-II gene ( Apoa2(c)). After AApoAII injection, amyloid deposition occurred rapidly and advanced in an accelerated manner, as observed in spontaneous senile amylo idosis in mice. However, the injection of denatured AApoAII, native apoA-II in high-density lipoprotein (HDL), and denatured apoA-II monomer, which ha ve the same primary structure but without a fibril conformation, did not in duce amyloidosis. No amyloid deposition was observed in mice having an amyl oid-resistant apoA-II gene (Apoa2(b)) even 3 months after AApoAII injection . Significantly less amyloid deposition was observed in mice having both ty pes of apoA-II genes heterozygously (Apoa2(b/c)). These findings suggest th at the nucleation-dependent polymerization found in vitro also occurs in vi vo, and that the fibril conformation is required for the injected amyloid f ibrils to act as seeds in vivo. Fibril conformation-dependent fibrillizatio n is proposed as a general model of the pathogenesis of various kinds of am yloidosis occurring in vivo; it may be useful in both elucidating the patho genesis of amyloidosis and developing effective therapeutic modalities to t reat this disease.