Mapping genetic modulators of amyloid plaque deposition in TgCRND8 transgenic mice.
Alzheimer's disease (AD) is a complex disorder for which various in vivo models exist. The TgCRND8 mouse, transgenic for the human amyloid precursor protein, is an aggressive early onset model of brain amyloid deposition. Preliminary studies revealed that when the transgene is expressed on an A/J genetic background, these mice not only survive longer but also deposit less parenchymal amyloid-beta (Abeta) peptides as compared to those on a C57BL/6 background. We performed a genome-wide study of an F2 intercross between TgCRND8 on an A/J background and C57BL/6 mice, to identify genetic modulators of amyloid accumulation and deposition. We identified four highly significant QTLs that together account for 55% of the phenotypic variance in the number of plaques (Thioflavin S). QTLs were found on the distal part of chromosome 4 with an LOD score of 8.1 at D4Mit251, on chromosome 11 with an LOD score of 5.5 at D11Mit242, on chromosome 9 with an LOD score of 5.0 at D9Mit336 and on the proximal part of chromosome 8 with an LOD score of 4.5 at D8Mit223. A/J alleles at these loci are protective and all decreased the amount of Abeta deposition. Interestingly, the QTL on chromosome 11 is also significantly linked to the levels of brain Abeta(42) and Abeta(40). Although these QTLs do not control the levels of plasmatic Abeta, other regions on chromosomes 1 and 6 show significant linkage. Further characterization of these QTL regions may lead to the identification of genes involved in the pathogenesis of AD.
Sebastiani
Giovanna
G
Neurochem Inc., 275 Armand-Frappier Blvd., Laval, Canada H7V 4A7. gsebastiani@neurochem.com
Krzywkowski
Pascale
P
Dudal
Sherri
S
Yu
Mathilde
M
Paquette
Julie
J
Malo
Danielle
D
Gervais
Francine
F
Tremblay
Patrick
P
D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian; D006224:Cricetinae; D003433:Crosses, Genetic; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D058225:Plaque, Amyloid / Q000235:genetics*; D040641:Quantitative Trait Loci; D019076:Transgenes
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor