Genetic background regulates β-amyloid precursor protein processing and β-amyloid deposition in the mouse

Emily J H Lehman, Laura Shapiro Kulnane, Yuan Gao, Michelle C. Petriello, Karen M. Pimpis, Linda Younkin, Georgia Dolios, Rong Wang, Steven G. Younkin, Bruce Lamb

Research output: Contribution to journalArticle

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Abstract

Alzheimer's disease (AD) is a multigenic neurodegenerative disorder characterized by distinct neuropathological hallmarks including deposits of the β-amyloid (Aβ) peptide. Aβ 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 Aβ metabolism is a common feature of AD, the relationship between the levels of Aβ and various APP products and the onset of AD remains unclear. We have undertaken a screen to characterize genetic factors that modify APP processing, Aβ metabolism and Aβ 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 Aβ in young animals varied by genetic background. Furthermore, we demonstrate that age-dependent Aβ deposition in the APP YAC transgenic model is dramatically altered depending on the congenic strain examined. These studies demonstrate that APP processing, Aβ metabolism and Aβ 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.

Original languageEnglish (US)
Pages (from-to)2949-2956
Number of pages8
JournalHuman Molecular Genetics
Volume12
Issue number22
DOIs
StatePublished - Nov 15 2003
Externally publishedYes

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Amyloid beta-Protein Precursor
Amyloid
Yeast Artificial Chromosomes
Alzheimer Disease
Serum Amyloid A Protein
Peptides
Inbred Strains Mice
Genetic Background
Amyloid Plaques
Protein C
Transgenes
Neurodegenerative Diseases
Transgenic Mice
Phenotype
Amino Acids
Brain

ASJC Scopus subject areas

  • Genetics

Cite this

Genetic background regulates β-amyloid precursor protein processing and β-amyloid deposition in the mouse. / Lehman, Emily J H; Kulnane, Laura Shapiro; Gao, Yuan; Petriello, Michelle C.; Pimpis, Karen M.; Younkin, Linda; Dolios, Georgia; Wang, Rong; Younkin, Steven G.; Lamb, Bruce.

In: Human Molecular Genetics, Vol. 12, No. 22, 15.11.2003, p. 2949-2956.

Research output: Contribution to journalArticle

Lehman, EJH, Kulnane, LS, Gao, Y, Petriello, MC, Pimpis, KM, Younkin, L, Dolios, G, Wang, R, Younkin, SG & Lamb, B 2003, 'Genetic background regulates β-amyloid precursor protein processing and β-amyloid deposition in the mouse', Human Molecular Genetics, vol. 12, no. 22, pp. 2949-2956. https://doi.org/10.1093/hmg/ddg322
Lehman, Emily J H ; Kulnane, Laura Shapiro ; Gao, Yuan ; Petriello, Michelle C. ; Pimpis, Karen M. ; Younkin, Linda ; Dolios, Georgia ; Wang, Rong ; Younkin, Steven G. ; Lamb, Bruce. / Genetic background regulates β-amyloid precursor protein processing and β-amyloid deposition in the mouse. In: Human Molecular Genetics. 2003 ; Vol. 12, No. 22. pp. 2949-2956.
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