Human Molecular Genetics Advance Access originally published online on September 23, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Human Molecular Genetics, 2003, Vol. 12, No. 22 2949-2956
DOI: 10.1093/hmg/ddg322
© 2003 Oxford University Press
Genetic background regulates ß-amyloid precursor protein processing and ß-amyloid deposition in the mouse
1Departments of Genetics and Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106, USA, 2Center for Human Genetics, University Memory and Aging Center and Ireland Cancer Center, University Hospitals of Cleveland, Cleveland, OH 44106, USA, 3Center for Neuroscience, Mayo Foundation for Medical Education and Research, Jacksonville, FL 32224, USA and 4Department of Human Genetics, Mount Sinai School of Medicine, New York, NY 10029, USA
Received June 27, 2003; Revised September 4, 2003; Accepted September 15, 2003
Alzheimer's disease (AD) is a multigenic neurodegenerative disorder characterized by distinct neuropathological hallmarks including deposits of the ß-amyloid (Aß) peptide. Aß 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 Aß metabolism is a common feature of AD, the relationship between the levels of Aß and various APP products and the onset of AD remains unclear. We have undertaken a screen to characterize genetic factors that modify APP processing, Aß metabolism and Aß 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 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 Aß in young animals varied by genetic background. Furthermore, we demonstrate that age-dependent Aß deposition in the APP YAC transgenic model is dramatically altered depending on the congenic strain examined. These studies demonstrate that APP processing, Aß metabolism and Aß 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.
* To whom correspondence should be addressed at: Department of Genetics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4955, USA. Tel: +1 2163682979; Fax: +1 2163683432; Email: btl{at}po.cwru.edu
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  G. Chen, K. S. Chen, D. Kobayashi, R. Barbour, R. Motter, D. Games, S. J. Martin, and R. G. M. Morris Active {beta}-Amyloid Immunization Restores Spatial Learning in PDAPP Mice Displaying Very Low Levels of {beta}-Amyloid J. Neurosci., March 7, 2007; 27(10): 2654 - 2662. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Sebastiani, P. Krzywkowski, S. Dudal, M. Yu, J. Paquette, D. Malo, F. Gervais, and P. Tremblay Mapping genetic modulators of amyloid plaque deposition in TgCRND8 transgenic mice Hum. Mol. Genet., August 1, 2006; 15(15): 2313 - 2323. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Qu, R. N. Rosenberg, L. Li, P. J. Boyer, and S. A. Johnston Gene Vaccination to Bias the Immune Response to Amyloid-{beta} Peptide as Therapy for Alzheimer Disease Arch Neurol, December 1, 2004; 61(12): 1859 - 1864. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Mann, F. E. Thorngate, Y. Katoh-Fukui, H. Hamanaka, D. L. Williams, S. Fujita, and B. T. Lamb Independent effects of APOE on cholesterol metabolism and brain A{beta} levels in an Alzheimer disease mouse model Hum. Mol. Genet., September 1, 2004; 13(17): 1959 - 1968. [Abstract] [Full Text] [PDF]
|
|