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

Ryman, Davis; Gao, Yuan; Lamb, Bruce T.

doi:10.1016/j.neurobiolaging.2007.02.017

« Previous Next »Neurobiology of Aging
Volume 29, Issue 8 , Pages 1190-1198, August 2008

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

Davis Ryman
- Lerner Research Institute, Cleveland Clinic Foundation, Department of Neurosciences, NC3-164, 9500 Euclid Avenue, Cleveland, OH 44195 USA
- Case Western Reserve University School of Medicine, Department of Genetics, 10900 Euclid Avenue, Cleveland, OH 44106-4955, USA
Yuan Gao
- Case Western Reserve University School of Medicine, Department of Genetics, 10900 Euclid Avenue, Cleveland, OH 44106-4955, USA
Bruce T. Lamb
- Lerner Research Institute, Cleveland Clinic Foundation, Department of Neurosciences, NC3-164, 9500 Euclid Avenue, Cleveland, OH 44195 USA
- Case Western Reserve University School of Medicine, Department of Genetics, 10900 Euclid Avenue, Cleveland, OH 44106-4955, USA
- Case Western Reserve University School of Medicine, Department of Neuroscience, 10900 Euclid Avenue, Cleveland, OH 44106-4955, USA
- Corresponding author at: Lerner Research Institute, Cleveland Clinic Foundation, Department of Neurosciences, NC3-164, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Tel.: +1 216 444 3592; fax: +1 216 444 7927.

Received 25 October 2006; received in revised form 23 January 2007; accepted 10 February 2007. published online 02 April 2007.

Abstract

Genetic studies have demonstrated very high heritability for Alzheimer's disease (AD) risk in humans; however, these genetic contributions have proven extremely challenging to map in large studies of AD patients. Processing of the amyloid precursor protein (APP) to produce amyloid-beta (Aβ) peptide is increasingly believed to be of central importance in AD pathogenesis. Intriguingly, mice from the C57BL/6J and DBA2/J inbred strains carrying the R1.40 APP transgene produce identical levels of unprocessed APP, but demonstrate significant, heritable differences in Aβ levels. To identify specific loci responsible for the observed genetic control of Aβ metabolism in this model system, we have performed a whole-genome quantitative trait locus (QTL) mapping experiment on a total of 516 animals from a C57BL/6J×DBA/2J intercross using a dense set of SNP genetic markers. Our studies have identified three loci on mouse chromosomes 1, 2, and 7 showing significant or suggestive associations with brain Aβ levels, several of which contain regions syntenic to previous reports of linkage in human AD.