In murine senile
amyloidosis, misfolded serum
apolipoprotein (
apo) A-II deposits as
amyloid fibrils (AApoAII) in a process associated with aging. Mouse strains carrying type C
apoA-II (APOA2C)
protein exhibit a high incidence of severe systemic
amyloidosis. Previously, we showed that N- and C-terminal sequences of
apoA-II protein are critical for polymerization into
amyloid fibrils in vitro. Here, we demonstrate that congenic mouse strains carrying type F
apoA-II (APOA2F)
protein, which contains four amino acid substitutions in the amyloidogenic regions of APOA2C, were absolutely resistant to
amyloidosis, even after induction of
amyloidosis by injection of AApoAII. In vitro fibril formation tests showed that N- and C-terminal APOA2F
peptides did not polymerize into
amyloid fibrils. Moreover, a C-terminal APOA2F
peptide was a strong inhibitor of nucleation and extension of
amyloid fibrils during polymerization. Importantly, after the induction of
amyloidosis, we succeeded in suppressing
amyloid deposition in senile
amyloidosis-susceptible mice by treatment with the C-terminal APOA2F
peptide. We suggest that the C-terminal APOA2F
peptide might inhibit further extension of
amyloid fibrils by blocking the active ends of nuclei (seeds). We present a previously unidentified model system for investigating inhibitory mechanisms against
amyloidosis in vivo and in vitro and believe that this system will be useful for the development of novel
therapies.