Identification of Loci Determining Susceptibility to Amyloid Precursor Protein Transgene Overexpression

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Researchers have discovered genetic loci responsible for determining susceptibility to the lethal effects of amyloid precursor protein transgene overexpression, a condition that can lead to central nervous system disorders and premature death in mice. The study found that FVB/N mice are more susceptible to the lethal effects of APP overexpression, while 129S6 mice are resistant. By analyzing crosses involving FVB/NCr and 129S6.Tg2576 mice, scientists identified significant linkage to loci on proximal chromosome 14 and on chromosome 9, which provide protection against the lethal effects of APP.

Key Takeaways:

  • Genetic loci on proximal chromosome 14 and on chromosome 9 play a crucial role in determining susceptibility to amyloid precursor protein transgene overexpression.
  • FVB/N mice are more susceptible to the lethal effects of APP overexpression, while 129S6 mice are resistant.
  • APP transgene-positive FVB129S6F1 mice are resistant to the lethal effects of APP overexpression.
  • Analysis of plasma A-beta peptide concentrations at 6 weeks in backcross offspring produced no significant linkage.
  • Elevation of human A-beta peptide concentrations by expression of mutant presenilin transgenes did not increase the proportion of mice dying prematurely.
  • The researchers identified segments homologous to regions on human chromosome 10 that have been linked to late onset Alzheimer's disease or to levels of A-beta peptide in plasma.
  • The study was published in Human Molecular Genetics (Identification of loci determining susceptibility to the lethal effects of amyloid precursor protein transgene overexpression. Hum Mol Genet, 2004;13(18):1989-1997).

Statistics:

  • 18% of FVB/N mice overexpressing human APP[subscript]695 died prematurely at an average age of 628 days.
  • 86% of 129S6 mice overexpressing human APP[subscript]695 survived beyond 18 months.
  • Significant linkage was found on proximal chromosome 14 and on chromosome 9, with a LOD score of 7.12 and 5.45, respectively.
  • The locus on chromosome 14 is located within a 5.2 cM region, while the locus on chromosome 9 is located within a 2.8 cM region.

Sources:

  • Human Molecular Genetics (Identification of loci determining susceptibility to the lethal effects of amyloid precursor protein transgene overexpression. Hum Mol Genet, 2004;13(18):1989-1997).
  • J. Krezowski et al. (2004) Identification of loci determining susceptibility to the lethal effects of amyloid precursor protein transgene overexpression. Hum Mol Genet, 13(18), 1989-1997.