Apolipoprotein E4 inhibits, and apolipoprotein E3 promotes neurite outgrowth in cultured adult mouse cortical neurons through the low-density lipoprotein receptor-related protein
Abstract
The apolipoprotein E4 (apoE4) genotype is a major risk factor for Alzheimer's disease (AD); however, the mechanism is unknown. We previously demonstrated that apoE isoforms differentially modulated neurite outgrowth in embryonic neurons and in neuronal cell lines. ApoE3 increased neurite outgrowth whereas apoE4 decreased outgrowth, suggesting that apoE4 may directly affect neurons in the brain. In the present study we examined the effects of apoE on neurite outgrowth from cultured adult mouse cortical neurons to examine if adult neurons respond the same way that embryonic cells do. The results from this study demonstrated that (1) cortical neurons derived from adult apoE-gene knockout (apoE KO) mice have significantly shorter neurites than neurons from adult wild-type (WT) mice; (2) incubation of cortical neurons from adult apoE KO mice with human apoE3 increased neurite outgrowth, whereas human apoE4 decreased outgrowth in a dose-dependent fashion; (3) the isoform specific effects were abolished by incubation of the neurons with either receptor associated protein (RAP) or lactoferrin, both of which block the interaction of apoE-containing lipoproteins with the low-density lipoprotein receptor-related protein (LRP). These data suggest a potential mechanism whereby apoE4 may play a role in regenerative failure and accelerate the development of AD.
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APOE has been shown to directly regulate neurite outgrowth in an isoform-dependent manner, with APOE4 inhibiting neurite extension in multiple systems.
“APOE has been shown to directly regulate neurite outgrowth in an isoform-dependent manner, with APOE4 inhibiting neurite extension in multiple systems (Hussain et al., 2013; Nathan et al., 2002; Zhao et al., 2017).”
From APOE3-Christchurch variant enhances neurovascular support functions of iPSC-derived mesenchymal stromal cells (2026) · cites this paper as Nathan et al., 2002
Most studies have shown that apoE3 augments neurite outgrowth to a greater extent than apoE4.
“Most studies have shown that apoE3 augments neurite outgrowth to a greater extent than apoE4 (Bellosta et al., 1995; Nathan et al., 1994; Nathan et al., 2002; Sun et al., 1998; Teter et al., 1999).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Nathan et al., 2002
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- Authors
- Nathan, B. P., Jiang, Y., Wong, G. K., Shen, F., Brewer, G. J., & Struble, R. G.
- Affiliations
- Eastern Illinois University (US)
- Quinnipiac University (US)
- SIU Medicine (US)
- Corresponding author
- Nathan, Britto P.
- Venue
- Brain Research
- Publisher
- Elsevier BV
- Published
- 2002-02
- Volume
- 928
- Issue
- 1-2
- Pages
- 96-105
- ISSN
- 0006-8993 (ISSN-L)
- OpenAlex
- W2039727377
- Cited by
- 169
- References
- 8
- Citations by year
- 2026: 9 · 2025: 1 · 2024: 4 · 2023: 4 · 2022: 3 · 2021: 8 · 2020: 5 · 2019: 2 · 2018: 5 · 2017: 4 · 2016: 1 · 2015: 2 · 2014: 5 · 2013: 8 · 2012: 7
- FWCI
- 7.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Research (publishedVersion)
- PubMed (publishedVersion)
- The Keep (Eastern Illinois University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- APOE ε4, apolipoprotein E3, neurite outgrowth, low density lipoprotein receptor-related protein, cortical neurons, Alzheimer's disease, APOE isoforms, receptor-associated protein, lactoferrin, ApoE-deficient mice, neuronal regeneration
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Cell Differentiation, Cells, Cultured, Cerebral Cortex, Dose-Response Relationship, Drug, Female, Immunohistochemistry, Lactoferrin, Male, Nerve Regeneration, Neuronal Plasticity, Neurites, Culture Media, Conditioned, Mice, Knockout, Cell Culture Techniques, Low Density Lipoprotein Receptor-Related Protein-1, LDL-Receptor Related Protein-Associated Protein, Mice, Apolipoprotein E3, Apolipoprotein E4
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