Genetic analysis of murine senile amyloidosis.
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.


METHODS
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.
Naiki
H
H
Department of Pathology, Fukui Medical School, Japan.
Higuchi
K
K
Shimada
A
A
Takeda
T
T
Nakakuki
K
K
D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000686:Amyloidosis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D004247:DNA / Q000032:analysis / Q000235:genetics; D003704:Dementia / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D005973:Glutamine / Q000032:analysis; D051379:Mice; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011392:Proline / Q000032:analysis; D011498:Protein Precursors / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000235:genetics*; D013050:Spectrometry, Fluorescence
D011498:Protein Precursors; D000685:Serum Amyloid A Protein; D005973:Glutamine; D004247:DNA; D011392:Proline