If the leery mother-in-law and the cautious would-be employer scrutinize the background of their prospect at hand, AD scientists would be well-advised to do the same. That, at least, is the view of Bruce Lamb at Case Western Reserve University in Cleveland, Ohio, and he has taken his own advice. At the 33rd Annual Meeting of the Society of Neuroscience held last month in New Orleans, Lamb described the latest analysis of his strains of congenic mice that differ by background only—a novel approach to study AD genetics that has not, as yet, been widely applied in the AD field.

In brief, the reasoning goes like this: Alzheimer’s is such a heterogeneous syndrome that even members of a single family carrying the same FAD mutation vary wildly in when they get the disease, how long and severe a course it takes, and in their symptoms and pathology. Assuming that the consequences of APP processing underlie AD pathogenesis, this striking variability means that other genes lurking in these patients’ backgrounds influence how the mutant APP is processed, how its cleavage products interact with other factors, and how the Aβ peptide is metabolized or deposited, Lamb told the audience. He also noted that the known AD genes represent only about 30 percent of AD risk; several human genetics labs have been trying for a decade to identify the rest.

The mouse situation mirrors the human in the sense that numerous strains of APP- and APP/PS-transgenic mice exist, but they vary widely in their phenotype and are difficult to compare directly (see Alzforum Research Model directory). Lamb and colleagues started a long-term project to identify modifying genes in AD without having to make prior mechanistic assumptions. They first packaged the entire human gene from various FAD mutations into yeast artificial chromosomes (YACs are basically large cloning vectors) and made transgenic mouse lines with them (Lamb et al., 1997, Lamb et al., 1999). At the meeting, Lamb focused on the APPSwe mutation, showing how extensive backcrossing of a YAC APPSwe line with three inbred mouse lines led to the creation of congenic strains that carry the same APPSwe gene on different genetic backgrounds (abstract 336.12, peruse abstracts at the SfN/ScholarOne website).

If the mutant APP was the only factor driving the phenotype, these strains should all be alike. Alas, they are not. While the congenic strains do show the same levels of APP holoprotein, at young ages they already differ in their production of C-terminal fragments (CTF) and in their brain and plasma Aβ levels. At the elderly age of 20 months, mice of one strain, called B6, have plaques littering their cortex, while those of another, D2, remain plaque-free despite their APPSwe gene. This suggests that background genes override the effects of the mutant APP gene in D2, Lamb said.

Lamb added that congenic mice also offer insight into another knotty problem—the interaction between genes and environmental confounders. Taking, for example, the link between cholesterol and amyloid deposition, Lamb asked whether background genes could account for some of the differences observed in the cholesterol response. Again, mice carrying the APPSwe gene on the B6 background developed increases in Aβ when fed a high-cholesterol diet, but the D2 background did not, suggesting that background genes influence cholesterol’s effect on Aβ metabolism. These are preliminary data.

In general, AD transgenic mice are on hybrid backgrounds. Many researchers using such strains have made anecdotal observations about marked background effects on the given phenotype they are studying, but most have viewed this as an experimental nuisance rather than an opportunity. Few, if any, have made a formal, systematic effort to capitalize on these background effects to identify novel modifying genes. Lamb’s group, with first author Emily Lehman, just published some of their data (Lehman et al., 2003), but for now, the identity of those modifying genes remains a mystery.—Gabrielle Strobel


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Paper Citations

  1. . Altered metabolism of familial Alzheimer's disease-linked amyloid precursor protein variants in yeast artificial chromosome transgenic mice. Hum Mol Genet. 1997 Sep;6(9):1535-41. PubMed.
  2. . Amyloid production and deposition in mutant amyloid precursor protein and presenilin-1 yeast artificial chromosome transgenic mice. Nat Neurosci. 1999 Aug;2(8):695-7. PubMed.
  3. . Genetic background regulates beta-amyloid precursor protein processing and beta-amyloid deposition in the mouse. Hum Mol Genet. 2003 Nov 15;12(22):2949-56. Epub 2003 Sep 23 PubMed.

Other Citations

  1. Alzforum Research Model

External Citations

  1. SfN/ScholarOne

Further Reading

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Primary Papers

  1. . Genetic background regulates beta-amyloid precursor protein processing and beta-amyloid deposition in the mouse. Hum Mol Genet. 2003 Nov 15;12(22):2949-56. Epub 2003 Sep 23 PubMed.