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Human Molecular Genetics Advance Access originally published online on July 14, 2004
Human Molecular Genetics 2004 13(18):1989-1997; doi:10.1093/hmg/ddh210
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Human Molecular Genetics, Vol. 13, No. 18 © Oxford University Press 2004; all rights reserved

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

Joseph Krezowski1,{dagger}, Danielle Knudson1,{dagger}, Christine Ebeling1, Rose Pitstick1, Ranjit K. Giri1, Dale Schenk2, David Westaway3, Linda Younkin4, Steven G. Younkin4, Karen Hsiao Ashe5 and George A. Carlson1,*

1McLaughlin Research Institute, 1520 23rd Street South, Great Falls, MT 59405, USA, 2Elan Pharmaceuticals, South San Francisco, CA 94080, USA, 3Centre for Neurodegenerative Diseases, Toronto, Ontario M5S 3H2, Canada, 4Mayo Clinic, Jacksonville, FL 32224, USA and 5Department of Neurology, University of Minnesota, Minneapolis, MN 55455, USA

Received April 12, 2004; Accepted July 1, 2004

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 Aß peptide amyloid plaques. 129S6 mice are resistant to the lethal effects of APP overexpression, allowing sufficient levels of Aß 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 Aß peptide in plasma. However, analysis of plasma Aß peptide concentrations at 6 weeks in backcross offspring produced no significant linkage. Similarly, elevation of human Aß 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 Aß.

* To whom correspondence should be addressed. Tel: +1 4064546044; Fax: +1 4064546019; Email: gac{at}po.mri.montana.edu


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