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Human Molecular Genetics Advance Access originally published online on June 19, 2006
Human Molecular Genetics 2006 15(15):2313-2323; doi:10.1093/hmg/ddl157
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Mapping genetic modulators of amyloid plaque deposition in TgCRND8 transgenic mice

Giovanna Sebastiani1,*, Pascale Krzywkowski1, Sherri Dudal1, Mathilde Yu1, Julie Paquette1, Danielle Malo2,3, Francine Gervais1,{dagger} and Patrick Tremblay1,{ddagger}

1 Neurochem Inc., 275 Armand-Frappier Blvd., Laval, Canada H7V 4A7, 2 Department of Experimental Medicine and 3 Department of Human Genetics, McGill University, Montreal, Canada H3A 1B1

* To whom correspondence should be addressed. Tel: +1 4506804500; Fax: +1 4506804506; Email: gsebastiani{at}neurochem.com

Received February 28, 2006; Revised April 24, 2006; Accepted June 15, 2006

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-ß (Aß) 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 Aß deposition. Interestingly, the QTL on chromosome 11 is also significantly linked to the levels of brain Aß42 and Aß40. Although these QTLs do not control the levels of plasmatic Aß, 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.

{dagger} Present address: Painceptor Pharma Corp., 7150 Albert-Einstein Ave., Suite 100, Saint-Laurent, Canada H4S 2C1.

{ddagger} Present address: Bioaxone Therapeutic Inc., 7150 Frederick-Banting Ave., Suite 200, Saint-Laurent, Canada H4S 2C1.


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