Genetic background regulates beta-amyloid precursor protein processing and beta-amyloid deposition in the mouse.
Alzheimer's disease (AD) is a multigenic neurodegenerative disorder characterized by distinct neuropathological hallmarks including deposits of the beta-amyloid (A beta) peptide. A beta 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 beta metabolism is a common feature of AD, the relationship between the levels of A beta 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 beta metabolism and A beta 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 A beta in young animals varied by genetic background. Furthermore, we demonstrate that age-dependent A beta deposition in the APP YAC transgenic model is dramatically altered depending on the congenic strain examined. These studies demonstrate that APP processing, A beta metabolism and A beta 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.
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D022202:Chromosomes, Artificial, Bacterial; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D014644:Genetic Variation; D007150:Immunohistochemistry; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D011233:Precipitin Tests; D011499:Protein Processing, Post-Translational; D013045:Species Specificity; D019076:Transgenes
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal