Expression in brain of amyloid precursor protein mutated in the alpha‐secretase site causes disturbed behavior, neuronal degeneration and premature death in transgenic mice.
Open accessAbstract
A double mutation in the alpha-secretase site in the betaA4 region of mouse amyloid precursor protein (APP) reduced its secretion from COS cells, polarized MDCK cells and rat primary neurons. Expression of this mutant in the brain of mice, using the neuron-specific elements of the mouse Thy-1 gene promoter, resulted in transgenic mice that became progressively hyperactive, displayed seizures and died prematurely. In three different transgenic lines the severity of the phenotype was related directly to the expression levels of the transgene, estimated by both mRNA and protein levels. In addition, homozygous mice derived from each transgenic strain showed more severe symptoms which also occurred earlier in life than in heterozygotes. The observed symptoms were, however, not essentially different in the different lines. Increased aggressiveness, disturbed responses to kainic acid and N-methyl-D-aspartate, neophobia and deficiency in exploratory behavior were demonstrated in these mice. In the brain, the observed neuropathological changes included necrosis, apoptosis and astrogliosis in the hippocampus, cortex and other areas. The data demonstrate that incomplete or incorrect alpha-secretase processing of APP results in severe neurotoxicity and that this effect is expressed in a dominant manner.
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Both models rely on transgene overexpression and familial mutations and are not well suited for studying causative events that lead to development of pathology in sporadic AD.
“Both models rely on transgene overexpression and familial mutations (such as ADAD mutations in 5xFAD mice and frontotemporal dementia mutations in PS19 mice) and are not well suited for studying the causative events that lead to the development of pathology in sporadic AD [44–47].”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [44]
The Discussion (page not available) describes a transgenic mouse model in which overexpression of mutant APP causes the observed phenotype. It does not characterize the 5xFAD or PS19 models, establish that their mutations are familial, or assess their suitability for studying the causes of sporadic AD. (LLM, conf=0.85)
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- Authors
- Moechars, D., Lorent, K., De Strooper, B., Dewachter, I., & Van Leuven, F.
- Affiliations
- KU Leuven (BE)
- Venue
- The EMBO Journal
- Published
- 1996-03-01
- Volume
- 15
- Issue
- 6
- Pages
- 1265-1274
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC450029
- OpenAlex
- W1512881390
- Cited by
- 201
- References
- 7
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 4 · 2023: 6 · 2022: 3 · 2021: 5 · 2020: 3 · 2019: 2 · 2018: 1 · 2017: 1 · 2016: 4 · 2015: 8 · 2014: 6 · 2013: 2 · 2012: 10
- FWCI
- 5.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Vlaamse regering
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- amyloid precursor protein, APP processing, transgenic mice, neurodegeneration, premature mortality, hyperactivity, seizures, neurotoxicity, dominant inheritance, apoptosis, astrocyte activation, behavioral abnormalities, kainic acid, NMDA
- MeSH terms
- Animals, Behavior, Animal, Brain, Brain Diseases, Metabolic, Hyperkinesis, Kainic Acid, Mice, Transgenic, Mutation, Neurons, Endopeptidases, Protein Processing, Post-Translational, Seizures, N-Methylaspartate, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Excitatory Amino Acid Agonists, Mice, Amyloid Precursor Protein Secretases
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