Inhibition of the canonical Wnt signaling pathway by apolipoprotein E4 in PC12 cells
Abstract
We examined the effect of the three human isoforms of apolipoprotein E (ApoE2, ApoE3, and ApoE4) on the canonical Wnt signaling pathway in undifferentiated PC12 cells. Addition of recombinant ApoE4 reduced Wingless‐Int7a‐stimulated gene expression at concentrations of 80 and 500 n m. Recombinant ApoE2 and ApoE3 were virtually inactive. Recombinant ApoE4 also inhibited Wnt signaling when combined with very low density lipoproteins (VLDLs) or in cells over‐expressing the low density lipoprotein receptor‐related protein, LRP6. In contrast, the enforced expression of LRP5 unmasked an inhibition by ApoE2 and ApoE3, which, however, were less effective than ApoE4 in inhibiting Wnt signaling. We also transfected PC12 cells with constructs encoding for the three human ApoE isoforms to examine whether endogenously expressed ApoE isoforms could modulate the Wnt pathway. Under these conditions, all three ApoE isoforms were able to inhibit Wnt signaling, although ApoE4 showed the greatest efficacy. Only the conditioned medium collected from cultures transfected with ApoE4 induced a significant inhibition of Wnt7a‐stimulated gene expression, confirming that ApoE4 has an extracellular action that is not shared by the other ApoE isoforms. We conclude that ApoE4 behaves as an inhibitor of the canonical Wnt pathway in a context‐independent manner.
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ApoE inhibits Wnt signaling through competitive binding to LRP receptors, with ApoE4 being a stronger inhibitor than ApoE3 and ApoE2.
“the inhibitory effect of ApoE on Wnt signaling, attributed to competitive binding to LRP receptors, has been reported before with ApoE4 being the stronger inhibitor compared to ApoE3 and ApoE2 (Caruso et al., 2006)”
From APOE3 Christchurch modulates β-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer’s cases (2024) · cites this paper as Caruso et al., 2006
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BackgroundInfluential
- Authors
- Caruso, A., Motolese, M., Iacovelli, L., Caraci, F., Copani, A., Nicoletti, F., Terstappen, G. C., Gaviraghi, G., & Caricasole, A.
- Affiliations
- Sapienza University of Rome (IT)
- University of Catania (IT)
- Istituto Neurologico Mediterraneo (IT)
- Siena Biotech (Italy) (IT)
- Corresponding author
- Nicoletti, Ferdinando
- ORCID
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2006-05-30
- Volume
- 98
- Issue
- 2
- Pages
- 364-371
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2140060167
- Cited by
- 101
- References
- 59
- Citations by year
- 2026: 1 · 2025: 8 · 2024: 5 · 2023: 9 · 2022: 3 · 2021: 7 · 2020: 6 · 2019: 4 · 2018: 2 · 2017: 6 · 2016: 3 · 2015: 4 · 2014: 7 · 2013: 3 · 2012: 7
- FWCI
- 2.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- APOE ε4, apolipoprotein E isoforms, Wnt/β-catenin signaling, Wnt7a, LRP6, LRP5, PC12 cells, neurogenesis inhibition, extracellular signaling, lipoproteins
- MeSH terms
- Animals, Apolipoproteins E, Culture Media, Plasmids, Transfection, Blotting, Western, Signal Transduction, PC12 Cells, Wnt Proteins, beta Catenin, Rats, Apolipoprotein E3, Apolipoprotein E4
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