Identification of loci determining susceptibility to the lethal effects of amyloid precursor protein transgene overexpression

Abstract

Phenotypes produced by expression of human amyloid precursor protein (APP) transgenes vary depending on the genetic background of the mouse. FVB/N mice overexpressing human APP695 develop a central nervous system disorder and die prematurely, precluding development of Abeta peptide amyloid plaques. 129S6 mice are resistant to the lethal effects of APP overexpression, allowing sufficient levels of Abeta expression for the development of amyloid plaques and age-dependent memory deficits. To identify the genes that determine susceptibility or resistance to APP we analyzed crosses involving FVB/NCr and 129S6.Tg2576 mice that overexpress 'Swedish' mutant (K670N, M671L) APP695. APP transgene-positive FVB129S6F1 (F1) mice are resistant to the lethal effects of APP overexpression, so FVBxF1 backcross and F2 intercross offspring were produced. Analysis of age of death as a quantitative trait revealed significant linkage to loci on proximal chromosome 14 and on chromosome 9; 129S6 alleles protect against the lethal effects of APP. Within the chromosome 14 interval are segments homologous to regions on human chromosome 10 that have been linked to late onset Alzheimer's disease or to levels of Abeta peptide in plasma. However, analysis of plasma Abeta peptide concentrations at 6 weeks in backcross offspring produced no significant linkage. Similarly, elevation of human Abeta peptide concentrations by expression of mutant presenilin transgenes did not increase the proportion of mice dying prematurely, suggesting that early death reflects effects of APP or fragments other than Abeta.

Aβ40 Inhibits Amyloid DepositionIn Vivo

“…Reduction in A␤ levels by increased ␣-secretase activity or by enhanced proteolysis of A␤ has been linked to prevention of high mortality in APP transgenic mice and Drosophila (Leissring et al, 2003;Etcheberrigaray et al, 2004;Finelli et al, 2004). Together, these studies provide indirect evidence that alterations in A␤ levels can modulate the premature-death phenotype, although one study suggests that this is not because of A␤ (Krezowski et al, 2004). Although it is difficult to completely exclude other transgenerelated and genetic background effects, our data suggest that an interaction between A␤40 and A␤42 is required for the premature-death phenotype.…”

Genetic loci modulating amyloid-beta levels in a mouse model of Alzheimer's disease

“…In one recent study, a QTL mapping approach was used to identify several loci modifying APP-dependent lethality (Krezowski et al 2004). To assess the F2 population for regional divergences from expected Hardy-Weinberg genotype ratios that may result from genes modifying survival, we performed a chi-square analysis comparing prevalence of observed genotypes with the expected values.…”

“…Prominent advantages of modeling AD genetics in the mouse include its short generation time and early disease onset, its similarity to human neurophysiology, the utility of genetically defined inbred strains in creating highly informative intercross populations, and the ability to isolate and reproducibly study specific candidate genes and regions through the eventual construction of congenic strains for defined genomic intervals. Krezowski et al (2004) used a mouse intercross QTL mapping approach to identify genetic loci modifying susceptibility to APP transgene-induced lethality, Brich et al (2003) performed a mouse genome scan for QTLs modifying tau phosphorylation, and Sebastiani et al (2006) recently published a mouse genome scan for amyloid pathology, detecting several QTLs modifying plaque deposition in an intercross using TgCRND8 transgenic mice from the C57BL/6J and A/J inbred strains.…”

A Two-Locus System Controls Susceptibility to Colitis-Associated Colon Cancer in Mice

“…Indeed, DSS treatment has been shown to cause permeabilization of the epithelial cell barrier resulting in increased cellular turnover to repair tissue damage, a response that may be under the control of Ccs4. It is also interesting to note that a similar two-locus system involving chromosome 9 and 14 has been shown to regulate differential brain toxicity of human amyloid precursor protein expressed in transgenic 129sv and FVB mice [32]. Although this two-locus system has been mapped in another strain pair, and with a low degree of resolution, it is nevertheless interesting to note that it regulates response to a toxic substance in the form of different degree to tissue damage.…”