Defective neuronal sprouting by human apolipoprotein E4 is a gain-of-negative function.
Abstract
The apolipoprotein E (apoE) epsilon 4 allele (apoE4) is a major risk factor for neurodegenerative conditions, including Alzheimer's disease (AD). A role for apoE in regeneration of synaptic circuitry after neural injury has been shown in several in vitro studies in which apoE3 supports neuronal sprouting better than apoE4. We evaluated sprouting in an in vitro mouse organotypic hippocampal slice culture system derived from transgenic mice expressing apoE3 or apoE4, in which apoE-dependent granule cell mossy fiber sprouting in the presence of apoE4 is only 51% of the level of apoE3. Sprouting supported by apoE4 had a dose response opposite that by supported by apoE3: although increasing E3 expression increased sprouting, increasing E4 expression decreased sprouting, suggesting that the defect in E4 in supporting neuronal sprouting is a gain-of-negative activity. These results may have important pharmacogenomic implications for AD therapies that modulate apoE expression levels.
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Some studies reported that apoE4 had detrimental effects on neurite outgrowth, others found no effects or even stimulating effects.
“While some studies reported that apoE4 had detrimental effects on neurite outgrowth (Teter et al., 2002), others found no effects (DeMattos et al., 1998) or even stimulating effects (Puttfarcken et al., 1997).”
From Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms (2014) · cites this paper as Teter et al., 2002
The effect of apoE4 on neurite outgrowth has been inconsistent among studies.
“However, the effect of apoE4 on neurite outgrowth has been inconsistent among studies (DeMattos et al., 1998; Puttfarcken et al., 1997; Teter et al., 2002).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Teter et al., 2002
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“In one sense, such conflicting data from in vivo studies reflect the inconsistent results obtained from in vitro experiments (DeMattos et al., 1998; Puttfarcken et al., 1997; Teter et al., 2002).”
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The presence of apoE4, not the absence of apoE3, contributes to AD pathology
Teter, B., Raber, J., Nathan, B., & Crutcher, K. A. (2002) · Journal of Alzheimer's Disease · doi:10.3233/jad-2002-4305 · Cited by 37 · see citing works
Self-citationApolipoprotein E ε4-related thickening of the cerebral cortex modulates selective attention
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- Authors
- Teter, B., Xu, P., Gilbert, J. R., Roses, A. D., Galasko, D., & Cole, G. M.
- Affiliations
- University of California, Los Angeles (US)
- Duke University (US)
- University of California San Diego (US)
- Corresponding author
- Teter, B.
- Venue
- Journal of Neuroscience Research
- Publisher
- Wiley
- Published
- 2002-04-05
- Volume
- 68
- Issue
- 3
- Pages
- 331-336
- ISSN
- 0360-4012 (ISSN-L)
- 1097-4547
- OpenAlex
- W2168746537
- Cited by
- 74
- References
- 12
- Citations by year
- 2025: 1 · 2022: 2 · 2021: 3 · 2019: 3 · 2018: 4 · 2017: 4 · 2016: 2 · 2015: 1 · 2014: 5 · 2012: 2
- FWCI
- 3.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuroscience Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (K01AG000962, P50AG016570, AG 16570)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- APOE ε4, apolipoprotein E3, nerve sprouting, mossy fiber sprouting, granule cells, hippocampal slice cultures, Alzheimer's disease, synaptic regeneration, pharmacogenomics, neurodegeneration
- MeSH terms
- Alzheimer Disease, Animals, Animals, Newborn, Apolipoproteins E, Cell Differentiation, Female, Heterozygote, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Neuronal Plasticity, Phenotype, Up-Regulation, Gene Expression Regulation, Developmental, Mossy Fibers, Hippocampal, Genetic Predisposition to Disease, Protein Isoforms, Growth Cones, Mice, Apolipoprotein E3, Apolipoprotein E4
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