Human Molecular Genetics Advance Access published online on September 23, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg322
© 2003 by Oxford University Press
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1 Departments of Genetics and Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106, USA; Center for Human Genetics, University Memory and Aging Center and Ireland Cancer Center, University Hospitals of Cleveland, Cleveland, Ohio 44106, USA
* To whom correspondence should be addressed. E-mail: btl{at}po.cwru.edu.
Alzheimer's disease (AD) is a multigenic neurodegenerative disorder characterized by distinct neuropathological hallmarks including deposits of the
Article
Genetic Background Regulates
-Amyloid Precursor Protein Processing and -Amyloid Deposition in the Mouse
2 Center for Neuroscience, Mayo Foundation for Medical Education and Research, Jacksonville, Florida 32224, USA
3 Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029, USA
4 Departments of Genetics and Neurosciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106-4955, USA; Center for Human Genetics, University Memory and Aging Center and Ireland Cancer Center, University Hospitals of Cleveland, Cleveland, Ohio 44106, USA
Abstract 
-amyloid (A) peptide. A is a 39- to 43-amino acid peptide derived from the proteolytic processing of the amyloid precursor protein (APP). While increasing evidence suggests that altered APP processing and A metabolism is a common feature of AD, the relationship between the levels of A and various APP products and the onset of AD remains unclear. We have undertaken a screen to characterize genetic factors that modify APP processing, A metabolism and A deposition in a genomic-based yeast artificial chromosome (YAC) transgenic mouse model of AD. A mutant human APP YAC transgene was transferred to three inbred mouse inbred strains. Despite similar levels of holo-APP expression in the congenic strains, the levels of APP C-terminal fragments as well as brain and plasma A in young animals varied by genetic background. Furthermore, we demonstrate that age-dependent A deposition in the APP YAC transgenic model is dramatically altered depending upon the congenic strain examined. These studies demonstrate that APP processing, A metabolism and A deposition are regulated by genetic background and that analysis of these phenotypes in mice should provide new insights into the factors that regulate AD pathogenesis.
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