| Alzheimer's disease (AD) is characterized by the presence of senile plaques formed by aggregation of the amyloid beta (Abeta) peptide, a processed product of the amyloid precursor protein (APP). The study of AD patient populations has demonstrated a highly significant degree of unexplained heritability for AD risk, and shown that several environmental factors, including hypercholesterolemia, can also influence the risk of developing AD. The Lamb lab has developed a unique mouse model system for the study of genetic modifiers of AD pathogenesis, by establishing a full genomic copy of R1.40, a mutant allele of APP known to result in familial human AD, on the genetic backgrounds of four different inbred strains of laboratory mice. Intriguingly, mice from the C57BL/6J and DBA2/.J genetic backgrounds carrying the R1.40 APP transgene produce identical levels of unprocessed APP, but demonstrate significant, heritable differences in brain Abeta levels. To identify specific loci responsible for the observed genetic control of Abeta metabolism in this model system, we have performed a whole-genome quantitative trait locus (QTL) mapping experiment on a total of 516 animals from a C57BL/6JxDBA/2J intercross using a dense set of 909 informative single nucleotide polymorphism (SNP) genetic markers. Our studies have identified three genetic loci on mouse chromosomes 1, 2, and 7 showing significant or suggestive associations with brain Abeta levels, several of which contain biologically interesting candidate AD genes and genomic regions orthologous to previous reports of linkage with human AD risk. We have additionally conducted studies to characterize the effects of dietary hypercholesterolemia on brain Abeta levels in the R1.40 inbred strains, and have shown that the effects of this environmental intervention are significantly modified by genetic background, potentially acting through diet-induced strain-specific differential gene expression observed specifically in the C57BL6/J strain. |
