Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes
Open accessAbstract
Significance: Susceptibility to Alzheimer’s disease (AD) is strongly controlled by apolipoprotein E ( APOE ) genotype. The E4 allele greatly increases risk whereas the E2 allele decreases risk, but it is not known how the APOE allele controls AD risk. In this paper, we report a novel role for APOE by showing that APOE2 enhances and APOE4 decreases the rate of synapse pruning and turnover in the brain by astrocytes. We also show that APOE alleles control the rate of accumulation of the complement C1q protein, which we hypothesize, reflects senescent synapse accumulation during normal brain aging and vulnerability of the aging brain to neurodegenerative diseases such as AD.
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Astrocytic apoE is involved in the regulation of synaptic pruning, suggesting a key role for astrocytic apoE in synaptic integrity.
“and that it is involved in the regulation of synaptic pruning, which suggests a key role for astrocytic apoE in synaptic integrity [49].”
From APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline (2021) · cites this paper as [49]
ApoE isoforms differentially affect synaptic pruning, with ApoE4 limiting the ability of astrocytes to prune synapses.
“ApoE isoforms differentially affect this process, with ApoE4 limiting the ability of astrocytes to prune synapses [76, 77].”
From ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease (2017) · cites this paper as [77]
In knock-in mice expressing human apoE variants, the apoE4 risk allele increases C1q accumulation relative to apoE2.
“in knock-in mice expressing human apoE variants, the apoE4 risk allele increases C1q accumulation relative to apoE2 (Chung et al., 2016).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Chung et al., 2016
C1q deposition is dependent on ApoE isoforms, with aged human ApoEε4 knock-in mice accumulating significantly more C1q in the hippocampus than ApoEε2 mice.
“another recent publication reported C1q deposition was dependent on ApoE isoforms, with aged human ApoEε4 knock-in mice accumulating significantly more C1q in the hippocampus than ApoEε2 mice.”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [166]
ApoEε2 enhanced synapse elimination by astrocytes while ApoEε4 prevented it.
“Additionally, ApoEε2 enhanced synapse elimination by astrocytes while ApoEε4 prevented it [166].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [166]
Microglia and astrocytes express complement, are highly phagocytic, and participate in synapse pruning.
“Since microglia and astrocytes, both of which express complement, are highly phagocytic and participate in synapse pruning (10, 43)”
From Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice (2017) · cites this paper as [43]
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- Authors
- Chung, W.-S., Verghese, P. B., Chakraborty, C., Joung, J., Hyman, B. T., Ulrich, J. D., Holtzman, D. M., & Barres, B. A.
- Affiliations
- Stanford Medicine (US)
- Hope Center for Neurological Disorders (US)
- Massachusetts General Hospital (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-08-24
- Volume
- 113
- Issue
- 36
- Pages
- 10186-10191
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5018780
- OpenAlex
- W2514110735
- Cited by
- 242
- References
- 50
- Citations by year
- 2026: 13 · 2025: 22 · 2024: 28 · 2023: 13 · 2022: 22 · 2021: 29 · 2020: 35 · 2019: 23 · 2018: 31 · 2017: 22 · 2016: 4
- FWCI
- 21.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Eye Institute (K99EY024690)
- HHS | National Institutes of Health (5 R21NS072556, R01 NS090934, R01 AG047644)
- National Research Foundation of Korea (NRF-2016M3C7A1905391, NRF-2016R1C1B3006969)
- 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
- apolipoprotein E, APOE isoforms, APOE ε4, APOE2, astrocytes, synaptic pruning, phagocytosis, C1q, complement system, Alzheimer's disease risk, hippocampus, neurodegeneration
- MeSH terms
- Alleles, Alzheimer Disease, Animals, Astrocytes, Gene Expression Regulation, Genotype, Hippocampus, Humans, Mice, Transgenic, Neuronal Plasticity, Phagocytosis, Synapses, Complement C1q, Genetic Predisposition to Disease, Mice, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2, Gene Knock-In Techniques
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