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ApoE4 Decreases Spine Density and Dendritic Complexity in Cortical Neurons In Vivo
Open accessAbstract
The three human alleles of apolipoprotein E (APOE) differentially influence outcome after CNS injury and affect one's risk of developing Alzheimer's disease (AD). It remains unclear how ApoE isoforms contribute to various AD-related pathological changes (e.g., amyloid plaques and synaptic and neuron loss). Here, we systematically examined whether apoE isoforms (E2, E3, E4) exhibit differential effects on dendritic spine density and morphology in APOE targeted replacement (TR) mice, which lack AD pathological changes. Using Golgi staining, we found age-dependent effects of APOE4 on spine density in the cortex. The APOE4 TR mice had significantly reduced spine density at three independent time points (4 weeks, 3 months, and 1 year, 27.7% ± 7.4%, 24.4% ± 8.6%, and 55.6% ± 10.5%, respectively) compared with APOE3 TR mice and APOE2 TR mice. Additionally, in APOE4 TR mice, shorter spines were evident compared with other APOE TR mice at 1 year. APOE2 TR mice exhibited longer spines as well as significantly increased apical dendritic arborization in the cortex compared with APOE4 and APOE3 TR mice at 4 weeks. However, there were no differences in spine density across APOE genotypes in hippocampus. These findings demonstrate that apoE isoforms differentially affect dendritic complexity and spine formation, suggesting a role for APOE genotypes not only in acute and chronic brain injuries including AD, but also in normal brain functions.
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“They compared dendritic spine number and length between neurons from mice lacking apoE altogether and mice in which a human APOE isoform replaced the mouse APOE gene, and demonstrated that the presence of any human apoE isoform led to increased spine number at 3 months of age in comparison to mice that lack apoE [Dumanis et al. (2009), their Fig.3A-C].”
From Differential Effects of ApoE Isoforms on Dendritic Spines In Vivo: Linking an Alzheimer's Disease Risk Factor with Synaptic Alterations (2010) · cites this paper as Dumanis et al. (2009)
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“One of the principal findings was that, at all ages examined, mice expressing APOE4 had significantly fewer dendritic spines in layer II/III cortical pyramidal neurons than mice expressing APOE2 or APOE3 [Dumanis et al. (2009), their Fig. 1, Fig. 3].”
From Differential Effects of ApoE Isoforms on Dendritic Spines In Vivo: Linking an Alzheimer's Disease Risk Factor with Synaptic Alterations (2010) · cites this paper as Dumanis et al. (2009)
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“The study by Dumanis et al. (2009) is the first to systematically compare dendritic spines in vivo in mice in which the human APOE2, APOE3, or APOE4 gene has been substituted into the mouse APOE locus.”
From Differential Effects of ApoE Isoforms on Dendritic Spines In Vivo: Linking an Alzheimer's Disease Risk Factor with Synaptic Alterations (2010) · cites this paper as Dumanis et al. (2009)
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“Dumanis et al. (2009) also found that spine length differed between mice expressing different APOE isoforms.”
From Differential Effects of ApoE Isoforms on Dendritic Spines In Vivo: Linking an Alzheimer's Disease Risk Factor with Synaptic Alterations (2010) · cites this paper as Dumanis et al. (2009)
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“In the 1-year-old cohort, the mice expressing the APOE4 gene had shorter spines than APOE2 and APOE3 mice [Dumanis et al. (2009), their Fig.3H].”
From Differential Effects of ApoE Isoforms on Dendritic Spines In Vivo: Linking an Alzheimer's Disease Risk Factor with Synaptic Alterations (2010) · cites this paper as Dumanis et al. (2009)
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“At 1 month of age, APOE2 mice had longer cortical spines than APOE3 and APOE4 mice [Dumanis et al. (2009), their Fig. 1 F-H].”
From Differential Effects of ApoE Isoforms on Dendritic Spines In Vivo: Linking an Alzheimer's Disease Risk Factor with Synaptic Alterations (2010) · cites this paper as Dumanis et al. (2009)
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“No differences in cortical spine density between APOE2 and APOE3 mice were observed [Dumanis et al. (2009), their Fig. 1, Fig. 3].”
From Differential Effects of ApoE Isoforms on Dendritic Spines In Vivo: Linking an Alzheimer's Disease Risk Factor with Synaptic Alterations (2010) · cites this paper as Dumanis et al. (2009)
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“This, however, does not rule out the possibility the structural synaptic changes might be present that have been observed by others (Dumanis et al., 2009).”
From Haploinsufficiency of Human APOE Reduces Amyloid Deposition in a Mouse Model of Amyloid-β Amyloidosis (2011) · cites this paper as Dumanis et al., 2009
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“Other previous studies also reported an association between the apoE4 and spine deficits in vivo (Basak and Kim, 2010; Dumanis et al., 2009; Ji et al., 2003; Wang et al., 2005).”
From Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms (2014) · cites this paper as Dumanis et al., 2009
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In the citing paper
“apolipoprotein (apo) E4–a major genetic risk factor for Alzheimer's disease–decreases spine density both in vivo [18], [19] and in vitro [20], [21]”
From Arf4 Determines Dentate Gyrus-Mediated Pattern Separation by Regulating Dendritic Spine Development (2012) · cites this paper as [18]
In the citing paper
“In another study, human APOE ε4 was found to reduce dendritic length and branching in the mouse cortex and hippocampus67.”
From Dendritic spine pathology in neuropsychiatric disorders (2011) · cites this paper as [67]
In the citing paper
“ApoE4 impairs synaptogenesis and decreases dendritic spine density in vivo and in vitro in primary neuronal cultures [72, 73].”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [73]
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Citations
Cites
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Self-citationDifferential Effects of Apolipoproteins E3 and E4 on Neuronal Growth in Vitro
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Regulation of Dendritic Spine Morphology by SPAR, a PSD-95-Associated RapGAP
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Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy
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Metadata
- Authors
- Dumanis, S. B., Tesoriero, J. A., Babus, L. W., Nguyen, M. T., Trotter, J. H., Ladu, M. J., Weeber, E. J., Turner, R. S., Xu, B., Rebeck, G. W., & Hoe, H.-S.
- Affiliations
- Georgetown University Medical Center (US)
- Georgetown University (US)
- University of South Florida (US)
- University of Illinois Chicago (US)
- Corresponding author
- Hoe, Hyang-Sook
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-12-02
- Volume
- 29
- Issue
- 48
- Pages
- 15317-15322
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2846754
- OpenAlex
- W2167047846
- Cited by
- 220
- References
- 31
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 10 · 2023: 8 · 2022: 15 · 2021: 16 · 2020: 18 · 2019: 14 · 2018: 14 · 2017: 10 · 2016: 17 · 2015: 7 · 2014: 19 · 2013: 18 · 2012: 15
- FWCI
- 8.84
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Georgetown University
- National Institutes of Health
- National Institute on Aging (R01AG026478, P01AG030128, R29AG014473, R03AG032330, R01AG014473, AG032330, AG026478, AG014473)
- National Institute of Neurological Disorders and Stroke (R01NS050596)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- apolipoprotein E, APOE ε4, APOE isoforms, dendritic spine density, dendritic complexity, cortical neurons, hippocampus, Alzheimer's disease risk, synaptic plasticity
- MeSH terms
- Age Factors, Analysis of Variance, Animals, Cells, Cultured, Cerebral Cortex, Dendrites, Embryo, Mammalian, Hippocampus, Humans, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Silver Staining, Rats, Sprague-Dawley, Protein Isoforms, Dendritic Spines, Mice, Rats, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2
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