The DOI matches its Crossref record; 50 of the 50 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source doesn’t support the claim as written.
In the citing paper
“Previous studies have shown that expression of human APOE4 can enhance C1q accumulation and increase astrocyte-mediated synaptic pruning in mouse brain (Chung, Verghese et al. 2016); similarly, iPSC-derived APOE4/E4 organoids feature enhanced apoptosis and impaired synaptic integrity compared to APOE3/E3 organoids (Zhao, Fu et al. 2020).”
From SORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain (2026) · cites this paper as Chung, Verghese et al. 2016
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
In the citing paper
“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 the citing paper
“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
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429
Alzheimer's Disease Is a Synaptic Failure
Selkoe, D. J. (2002) · Science · doi:10.1126/science.1074069 · Cited by 4,420
Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner
Schafer, D. P., Lehrman, E. K., Kautzman, A. G., Koyama, R., Mardinly, A. R., Yamasaki, R., Ransohoff, R. M., Greenberg, M. E., Barres, B. A., & Stevens, B. (2012) · Neuron · doi:10.1016/j.neuron.2012.03.026 · Cited by 4,089
Self-citationApolipoprotein E: Cholesterol Transport Protein with Expanding Role in Cell Biology
Mahley, R. W. (1988) · Science · doi:10.1126/science.3283935 · Cited by 4,028
Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue.
McCarthy, K. D., & de Vellis, J. (1980) · The Journal of Cell Biology · doi:10.1083/jcb.85.3.890 · Cited by 3,845
Complement and microglia mediate early synapse loss in Alzheimer mouse models
Hong, S., Beja-Glasser, V. F., Nfonoyim, B. M., Frouin, A., Li, S., Ramakrishnan, S., Merry, K. M., Shi, Q., Rosenthal, A., Barres, B. A., et al. (2016) · Science · doi:10.1126/science.aad8373 · Cited by 3,343 · cited 2×
“Moreover, a recent study has shown that the profound loss of synapses at the early stages of AD could be prevented by blocking activation of the complement cascade (38).”
BackgroundSelf-citationThe Classical Complement Cascade Mediates CNS Synapse Elimination
Stevens, B., Allen, N. J., Vazquez, L. E., Howell, G. R., Christopherson, K. S., Nouri, N., Micheva, K. D., Mehalow, A. K., Huberman, A. D., Stafford, B., et al. (2007) · Cell · doi:10.1016/j.cell.2007.10.036 · Cited by 3,313
Self-citationCahoy, J. D., Emery, B., Kaushal, A., Foo, L. C., Zamanian, J. L., Christopherson, K. S., Xing, Y., Lubischer, J. L., Krieg, P. A., Krupenko, S. A., et al. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4178-07.2008 · Cited by 3,129
Self-citationProtective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease
Corder, E. H., Saunders, A. M., Risch, N. J., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Rimmler, J. B., Locke, P. A., Conneally, P. M., Schmader, K. E., et al. (1994) · Nature Genetics · doi:10.1038/ng0694-180 · Cited by 1,920
Research works printed but not linked: 1
- B Teter, Apolipoprotein E isotype-specific effects in neurodegeneration. Alzheimers Rep 3, 199–212 (2000).
Cited by
Sorted by citations
Microglia in Alzheimer’s disease
Hansen, D. V., Hanson, J. E., & Sheng, M. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201709069 · Cited by 1,935
“Interestingly, in knock-in mice expressing human apoE variants, the apoE4 risk allele increases C1q accumulation relative to apoE2 (Chung et al., 2016).”
BackgroundAPOE and Alzheimer’s disease: Advances in genetics, pathophysiology, and therapeutic approaches
Serrano-Pozo, A., Das, S., & Hyman, B. T. (2021) · The Lancet Neurology · doi:10.1016/s1474-4422(20)30412-9 · Cited by 1,037
Self-citationInterplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight
Shi, Y., & Holtzman, D. M. (2018) · Nature Reviews Immunology · doi:10.1038/s41577-018-0051-1 · Cited by 595
Self-citationComplement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice
Shi, Q., Chowdhury, S., Ma, R., Le, K. X., Hong, S., Caldarone, B. J., Stevens, B., & Lemere, C. A. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf6295 · Cited by 593
“Given that microglia and astrocytes, both of which express complement, are highly phagocytic and participate in synapse pruning (10, 43), our findings that C3 deficiency protected against hippocampal synaptic decline in two mouse models (C3 KO and APP/PS1;C3 KO) suggest that complement C3 or its downstream activation…”
BackgroundWerneburg, S., Jung, J., Kunjamma, R. B., Ha, S.-K., Luciano, N. J., Willis, C. M., Gao, G., Biscola, N. P., Havton, L. A., Crocker, S. J., et al. (2020) · Immunity · doi:10.1016/j.immuni.2019.12.004 · Cited by 440
Metadata
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
