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Enhanced Amyloidogenic Processing of the β-Amyloid Precursor Protein in Gene-targeted Mice Bearing the Swedish Familial Alzheimer's Disease Mutations and a “Humanized” Aβ Sequence
Open accessAbstract
The processing of the beta-amyloid precursor protein (APP) in vivo has been characterized in a novel animal model that recapitulates, in part, the APP genotype of a familial form of Alzheimer's disease (AD). A gene-targeting strategy was used to introduce the Swedish familial AD mutations and convert mouse Abeta to the human sequence. The mutant APP is expressed at normal levels in brain, and cleavage at the mutant beta-secretase site is both accurate and enhanced. Furthermore, human Abeta production is significantly increased to levels 9-fold greater than those in normal human brain while nonamyloidogenic processing is depressed. The results on Abeta production extend similar findings obtained in cell culture to the brain of an animal and substantiate Abeta as a etiological factor in Swedish familial AD. These animals provide several distinguishing features over others created by conventional transgenic methodologies. The spatial and temporal expression patterns of human Abeta are expected to be faithfully reproduced because the gene encoding the mutant APP remains in its normal chromosomal context. Thus, the neuropathological consequences of human Abeta overproduction can be evaluated longitudinally in the absence of potential mitigating effects of APP overexpression or presence of the mouse Abeta peptide.
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“To overcome these issues, KI mouse models with familial AD mutations have been generated [10, 24, 31, 32].”
From Amyloid-β plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer’s disease (2019) · cites this paper as [24]
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“These genetic findings led to several transgenic mouse models that successfully recapitulated Aβ plaque formation, increasing support for the hypothesis (Table 1) [23–29].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [28]
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Metadata
- Authors
- Reaume, A. G., Howland, D. S., Trusko, S. P., Savage, M. J., Lang, D. M., Greenberg, B. D., Siman, R., & Scott, R. W.
- Corresponding author
- Scott, Richard W.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1996-09
- Volume
- 271
- Issue
- 38
- Pages
- 23380-23388
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2001834310
- Cited by
- 150
- References
- 69
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 4 · 2023: 2 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 3 · 2017: 6 · 2016: 2 · 2015: 3 · 2014: 7 · 2013: 7 · 2012: 8
- FWCI
- 5.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
- amyloid precursor protein, amyloidogenic processing, gene-targeted mice, animal models of Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Animals, Base Sequence, Brain Chemistry, Chimera, Disease Models, Animal, Genotype, Humans, Molecular Sequence Data, Mutation, Peptide Fragments, Endopeptidases, Protein Processing, Post-Translational, Sweden, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Gene Targeting, Mice, Amyloid Precursor Protein Secretases
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