Background: Recent studies have suggested that not only the genotypes of apolipoprotein A-II, the precursor protein of murine senile amyloid fibrils, but also other genetic factors may contribute to the pathogenesis of murine senile amyloidosis.
Experimental design: We investigated the mode of inheritance of murine senile amyloidosis, using 12-month-old and 14-month-old F1, F2 hybrids and backcrosses between SAM-P/1 and SAM-R/1. In SAM-P/1, the senescence process is accelerated and senile amyloidosis is evident, whereas in SAM-R/1, there is a normal aging process and no evidence of senile amyloidosis. In SAM-P/1 and SAM-R/1, the genotypes of apolipoprotein A-II are Gln/Gln and Pro/Pro, respectively, identified by restriction fragment length polymorphism of the apolipoprotein A-II gene for the restriction enzyme Cfr13I.
Results: Among hybrids and backcrosses, no senile amyloidosis was observed histopathologically, in Pro/Pro-type strains. Mild senile amyloidosis sparing the liver and spleen was observed in a significant percentage of Pro/Gln-type strains. Practical senile amyloidosis involving the liver and spleen was observed in all of the Gln/Gln-type strains. Quantitative fluorometric analysis with thioflavine T (Naiki H, Higuchi K, Matsushima K, Shimada A, Chen W-H, Hosokawa M, et al. Lab Invest 1990;62:768-73) revealed that the degree of murine senile amyloid fibril deposition was significantly decreased in the Gln/Gln-type hybrid and backcross strains, as compared with findings in SAM-P/1 and the degree of manifestation of accelerated senescence was significantly lower in the Gln/Gln-type hybrid and backcross strains than in the SAM-P/1.
Conclusions: Murine senile amyloidosis is linked to the molecular type of apolipoprotein A-II (i.e., Gln-type apolipoprotein A-II), and is transmitted as an autosomal dominant manner with incomplete penetrance. The severity of murine senile amyloidosis is far more advanced in Gln/Gln-type strains than in Pro/Gln-type strains. Other genetic factors that determine the manifestation of accelerated senescence, may significantly contribute to the degree of murine senile amyloidosis.