Genetic background regulates -amyloid precursor protein processing and -amyloid deposition in the mouse
Abstract
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.
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The R1.40 transgene is a full genomic copy of human APP carrying the K670M/N671L mutation.
“The R1.40 transgene is a full genomic copy of human APP (carried on a 650-kb yeast artificial chromosome clone) carrying the K670M/N671L familial AD mutation associated with early-onset familial AD.”
From CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid Deposition in Two Alzheimer's Disease Mouse Models (2010) · cites this paper as [25]
The “Generation of R1.40 congenic strains” section says R1.40 contains the entire human APP gene on a YAC, but gives the mutation as K670N/M671L, not K670M/N671L. The Introduction identifies it as the Swedish familial AD mutation. The passages found do not specify a 650-kb YAC. (LLM, conf=0.90)
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Cites
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- Authors
- Lehman, E. J. H.
- Affiliations
- University Hospitals of Cleveland (US)
- Corresponding author
- Lehman, E. J.H.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2003-09-18
- Volume
- 12
- Issue
- 22
- Pages
- 2949-2956
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2137760199
- Cited by
- 85
- References
- 4
- Citations by year
- 2024: 2 · 2023: 4 · 2022: 2 · 2020: 3 · 2019: 3 · 2018: 4 · 2017: 2 · 2016: 4 · 2015: 6 · 2014: 4 · 2013: 3 · 2012: 2
- FWCI
- 2.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association
- American Health Assistance Foundation
- National Institutes of Health (CA43703, AG10491, AG08012)
- National Institute on Aging (AG14451, P01AG010491, AG-08012, AG10491, P50AG008012)
- National Cancer Institute (CA 43703, P30CA043703)
- National Institute of General Medical Sciences (GM-08613, T32GM008613)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, amyloid precursor protein, amyloid-beta, APP processing, amyloid-beta deposition, genetic background, inbred mouse strains, congenic strains, APP C-terminal fragments, genetic modifiers
- MeSH terms
- Alzheimer Disease, Animals, Antibodies, Monoclonal, Brain, Enzyme-Linked Immunosorbent Assay, Gene Expression Regulation, Immunohistochemistry, Mice, Transgenic, Precipitin Tests, Protein Processing, Post-Translational, Species Specificity, Mass Spectrometry, Genetic Variation, Blotting, Western, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Transgenes, Chromosomes, Artificial, Bacterial, Mice
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