Characterization of transgenic mice expressing apolipoprotein E4(C112R) and apolipoprotein E4(L28P; C112R)
Abstract
Apolipoprotein E (ApoE), which is genetically polymorphic, is a constituent of different lipoproteins. Two variants, ApoE4(C112R) and ApoE4(L28P; C112R) have been linked to the risk of developing Alzheimer's disease. Transgenic mice carrying ApoE4(C112R) (AD71) and ApoE4(L28P; C112R) (AD61) were generated and compared to wild-type mice. The use of glial fibrillary acidic protein as promoter led to transgene expression mainly in glial cells but also in neurons. Transgene protein levels were approximately three-and-a-half-fold that of endogenous ApoE in the glial fibrillary acidic protein-ApoE4(C112R) (AD71) and nearly twofold in the glial fibrillary acidic protein-ApoE4(L28P; C112R) (AD61) mouse lines. Neither transgenic mouse differed from wild-type in cognitive tests at the age of approximately one-and-a-half years. The locomotor activity of AD61 mice was similar to controls, whereas AD71 mice exhibited a clearly reduced level of motor activity. Immunohistological and biochemical brain protein analyses revealed no difference between strains.Thus, in the absence of morphological changes over-expression of ApoE4(C112R) on a background of endogenous mouse ApoE, may result in behavioral deficits while for the ApoE4(L28P; C112R) transgene higher expression might be required or some compensatory mechanisms might protect these animals from the behavioral abnormalities.
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Transgenic mice expressing apoE4[L28P] and wild-type apoE4 under the glial fibrillary acidic protein promoter did not differ from non-transgenic mice in cognitive tests and showed no change in immunohistological and biochemical brain protein analyses.
“Neither transgenic mouse differed from non-transgenic mice in cognitive tests, nor did they show any change in immunohistological and biochemical brain protein analyses, a finding that is in conflict with the established association of apoE4 and AD in humans (61).”
From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [61]
The differences among the study of Huber et al. and other studies of apoE4 transgenic mice, including the presence or absence of endogenous mouse apoE and the different cellular expression sites for the apoE transgenes (glia versus neurons), seem to be critical for the development of an Alzheimer disease phenotype in mice.
“Therefore, the number of important differences among the study of Huber et al. (61) and other studies of apoE4 transgenic mice, including the presence or absence of endogenous mouse apoE, which could compensate or mask certain biological effects as well as the different cellular expression sites for the apoE transgenes (glia versus neurons), seem to be critical for the development of an AD pheno”
From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [61]
Previous attempts to model the effect of apoE4[L28P] in experimental animals have yielded conflicting results.
“Although the genetic association of apoE4 and, more specifically, apoE4[L28P] with LOAD has been established, previous attempts to model this effect in experimental animals have yielded conflicting results.”
From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [61]
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Aβ42 neurotoxicity in primary co-cultures: effect of apoE isoform and Aβ conformation
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Introducing Human <i>APOE</i> into A<i>β</i> Transgenic Mouse Models
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- Authors
- Huber, G., März, W., Martin, J. R., Malherbe, P., Richards, J. G., Sueoka, N., Ohm, T., & Hoffmann, M. M.
- Affiliations
- F. Hoffmann-La Roche AG (CH)
- University of Freiburg (DE)
- University of Colorado Boulder (US)
- Stiftung Charité (DE)
- Corresponding author
- Huber, G
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2000-10
- Volume
- 101
- Issue
- 1
- Pages
- 211-218
- ISSN
- 0306-4522 (ISSN-L)
- OpenAlex
- W1973723157
- Cited by
- 20
- References
- 5
- Citations by year
- 2022: 1 · 2021: 2 · 2020: 2 · 2015: 1 · 2014: 2
- FWCI
- 0.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- 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
- apolipoprotein E, transgenic mice, Alzheimer's disease risk, glial fibrillary acidic protein promoter, motor activity, cognitive function, behavioral deficits, compensatory mechanisms, lipoproteins
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Brain, Gene Expression Regulation, Mice, Transgenic, Motor Activity, Nerve Tissue Proteins, Neuroglia, Neurons, Phenotype, Risk Factors, Transgenes, Protein Isoforms, Mice, Apolipoprotein E4
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