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Human Molecular Genetics Advance Access published online on June 19, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl157
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received February 28, 2006
Revised June 15, 2006
Accepted June 15, 2006

Article

Mapping genetic modulators of amyloid plaque deposition in TgCRND8 transgenic mice

Giovanna Sebastiani 1 *, Pascale Krzywkowski 1, Sherri Dudal 1, Mathilde Yu 1, Julie Paquette 1, Danielle Malo 2, Francine Gervais 1, and Patrick Tremblay 1

1 Neurochem Inc., 275 Armand Frappier, Laval, H7V 4A7 Canada
2 Departments of Experimental Medicine and Human Genetics, McGill University, Montreal, H3A 1B1 Canada

* To whom correspondence should be addressed.
Giovanna Sebastiani, E-mail: gsebastiani{at}neurochem.com


  Abstract

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} (A{beta}) 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 a LOD score of 8.1 at D4Mit251, on chromosome 11 with a LOD score of 5.5 at D11Mit242, on chromosome 9 with a LOD score of 5.0 at D9Mit336, and on the proximal part of chromosome 8 with a LOD score of 4.5 at D8Mit223. A/J alleles at these loci are protective and all decreased the amount of A{beta} deposition. Interestingly, the QTL on chromosome 11 is also significantly linked to the levels of brain A{beta}42 and A{beta}40. Although these QTLs do not control the levels of plasmatic A{beta}, 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.


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