The DOI matches its Crossref record; 103 of the 104 references it cites were found in a registry or an index.
Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma
Open accessAbstract
The apolipoprotein E4 (APOE4) allele is associated with an increased risk of Alzheimer disease and a decreased risk of glaucoma, but the underlying mechanisms remain poorly understood. Here, we found that in two mouse glaucoma models, microglia transitioned to a neurodegenerative phenotype characterized by upregulation of Apoe and Lgals3 (Galectin-3), which were also upregulated in human glaucomatous retinas. Mice with targeted deletion of Apoe in microglia or carrying the human APOE4 allele were protected from retinal ganglion cell (RGC) loss, despite elevated intraocular pressure (IOP). Similarly to Apoe-/- retinal microglia, APOE4-expressing microglia did not upregulate neurodegeneration-associated genes, including Lgals3, following IOP elevation. Genetic and pharmacologic targeting of Galectin-3 ameliorated RGC degeneration, and Galectin-3 expression was attenuated in human APOE4 glaucoma samples. These results demonstrate that impaired activation of APOE4 microglia is protective in glaucoma and that the APOE-Galectin-3 signaling can be targeted to treat this blinding disease.
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
“Thus, APOE4 converges to impair the MGnD response to neurodegeneration, which plays a protective role in glaucoma 14 and is detrimental in AD.”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [14]
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
“We recently showed impaired MGnD responses in APOE4 -KI glaucoma mice, similar to Apoe -/-mice 14 .”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [14]
The cited source says what the claim attributes to it.
In the citing paper
“We recently demonstrated that APOE4 impairs the response of neurodegenerative retinal microglia via LGALS3 signaling associated with neuroprotection in glaucoma 14 .”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [14]
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
Neurotoxic reactive astrocytes are induced by activated microglia
Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W.-S., Peterson, T. C., et al. (2017) · Nature · doi:10.1038/nature21029 · Cited by 7,971
Global Prevalence of Glaucoma and Projections of Glaucoma Burden through 2040
Tham, Y.-C., Li, X., Wong, T. Y., Quigley, H. A., Aung, T., & Cheng, C.-Y. (2014) · Ophthalmology · doi:10.1016/j.ophtha.2014.05.013 · Cited by 7,159
A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease
Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., Ulland, T. K., David, E., Baruch, K., Lara-Astaiso, D., Toth, B., et al. (2017) · Cell · doi:10.1016/j.cell.2017.05.018 · Cited by 5,493
Strittmatter, W. J., Saunders, A. M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G. S., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.5.1977 · Cited by 4,268
Association of apolipoprotein E allele ϵ4 with late‐onset familial and sporadic Alzheimer's disease
Saunders, A. M., Strittmatter, W. J., Schmechel, D., St. George-Hyslop, P. H., Pericak-Vance, M. A., Joo, S. H., Rosi, B. L., Gusella, J. F., Crapper-MacLachlan, D. R., Alberts, M. J., et al. (1993) · Neurology · doi:10.1212/wnl.43.8.1467 · Cited by 3,786
TREM2 Variants in Alzheimer's Disease
Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J. S. K., Younkin, S., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211851 · Cited by 3,020
Krasemann, S., Madore, C., Cialic, R., Baufeld, C., Calcagno, N., El Fatimy, R., Beckers, L., O’Loughlin, E., Xu, Y., Fanek, Z., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.08.008 · Cited by 2,979
Self-citationMicroglia Function in the Central Nervous System During Health and Neurodegeneration
Colonna, M., & Butovsky, O. (2017) · Annual Review of Immunology · doi:10.1146/annurev-immunol-051116-052358 · Cited by 2,894
Self-citationMicroglia promote learning-dependent synapse formation through brain-derived neurotrophic factor
Parkhurst, C. N., Yang, G., Ninan, I., Savas, J. N., Yates, J. R., Lafaille, J. J., Hempstead, B. L., Littman, D. R., & Gan, W.-B. (2013) · Cell · doi:10.1016/j.cell.2013.11.030 · Cited by 2,599
Variant of TREM2 Associated with the Risk of Alzheimer's Disease
Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P. V., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A. I., Lah, J. J., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211103 · Cited by 2,558
Flagged first, then by citations
1 of the 104 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Items 101–130 of 130
Xue, Y., & Margeta, M. A. (2025) · American Journal of Ophthalmology Case Reports · doi:10.1016/j.ajoc.2025.102325
Self-citationApoE and Brain Synaptic Dynamics
Huang, Z. (2025) · Springer eBooks · doi:10.1007/978-3-031-52641-1_68-1
Kageyama, M., Ohashi, K., & Ota, T. (2025) · Scientific Reports · doi:10.1038/s41598-025-09503-z
Andries, L., Kancheva, D., Masin, L., Scheyltjens, I., Van Hove, H., Vlaminck, K. D., Bergmans, S., Claes, M., Groef, L. D., Moons, L., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23167834
Andries, L., Kancheva, D., Masin, L., Scheyltjens, I., Hove, H. V., Vlaminck, K. D., Bergmans, S., Claes, M., Groef, L. D., Moons, L., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23167825
Andries, L., Kancheva, D., Masin, L., Scheyltjens, I., Hove, H. V., Vlaminck, K. D., Bergmans, S., Claes, M., Groef, L. D., Moons, L., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23167828
Andries, L., Kancheva, D., Masin, L., Scheyltjens, I., Hove, H. V., Vlaminck, K. D., Bergmans, S., Claes, M., Groef, L. D., Moons, L., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23167837
Shi, H., Yin, Z., Koronyo, Y., Fuchs, D.-T., Sheyn, J., Davis, M. R., Wilson, J. W., Margeta, M. A., Pitts, K. M., Herron, S., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21069636
Self-citationAndries, L., Kancheva, D., Masin, L., Scheyltjens, I., Van Hove, H., Vlaminck, K. D., Bergmans, S., Claes, M., Groef, L. D., Moons, L., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23167831
Andries, L., Kancheva, D., Masin, L., Scheyltjens, I., Hove, H. V., Vlaminck, K. D., Bergmans, S., Claes, M., Groef, L. D., Moons, L., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23167816
Rovere, G., Matas, Y. C., Vidal‐Villegas, B., Bernal-Garro, J. M., Sobrado‐Calvo, P., Salinas-Navarro, M., Nucci, C., Villegas‐Pérez, M. P., Vidal‐Sanz, M., Agudo‐Barriuso, M., et al. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27031502
Santamaría-Muñoz, D., Reyes, R. V., Krueger, M. R., García‐Llorca, A., Marsh-Armstrong, B., Duan, X., Hu, Y., Welsbie, D. S., Marsh‐Armstrong, N., Sanz, E., et al. (2026) · Journal of Neuroinflammation · doi:10.1186/s12974-026-03707-4
Zhang, W., Bian, B., Ren, C., Chen, M. E., Fang, Y., Zhou, Y., Zhang, H., Li, B., Liu, H., Zhang, X., et al. (2026) · Neurobiology of Disease · doi:10.1016/j.nbd.2026.107295
St6gal1-mediated sialylation protects retinal ganglion cells by restraining microglial phagocytosis
Liu, L., Tang, J., Zhang, Q., Liu, Z., Qiu, Y., Zhang, B., Liu, Y., Zhuo, Y., & Li, Y. (2026) · Journal of Neuroinflammation · doi:10.1186/s12974-026-03736-z
Self-citationTao, L., Qin, J., Zhang, F., Tao, T., Tang, W., Cai, X., Tao, L., Wang, X., & Jiang, Z. (2026) · Materials Today Bio · doi:10.1016/j.mtbio.2026.102974
Li, X., Fan, N., Yan, Y., Ren, M., Wu, H., & Dong, K. (2026) · Journal of Neuroinflammation · doi:10.1186/s12974-026-03762-x
Zhang, X., Wang, X., Zhu, H., Yu, H., Fu, L., Shu, W., Ye, X., Lim, Z., Saeed, S., Nguyen, H. L., et al. (2026) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2026.101467
Glaucoma and Autoimmunity: Immunopathogenic Mechanisms and Emerging Immunomodulatory Therapies
Wang, M., Liu, C., & Wei, X. (2026) · Biomedicines · doi:10.3390/biomedicines14061209
Microglial regulation of synaptic plasticity in transsynaptic degeneration of glaucoma
He, Y., Dai, Y., Wu, Y., Xu, Z., & Lu, X. (2026) · Frontiers in Neuroscience · doi:10.3389/fnins.2026.1828085
Li, H., & Hong, X. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.11.731044
Longitudinal assessment of intraocular pressure in the 5xFAD mouse model of Alzheimer's disease
Rubinshtein, R., Obied, B., Salti, T., König, A. I., Zahavi, A., & Goldenberg‐Cohen, N. (2026) · Frontiers in Neurology · doi:10.3389/fneur.2026.1858031
Ji, Y., Liu, S., Zhang, Y., Jq, Z., Huang, C., ZHAO, Y., Xia, J., Mu, W., Yao, J. L., & Yan, B. (2026) · MedComm · doi:10.1002/mco2.70879
Rombaut, A., Wang, L., Lardner, E., Wong, R. C., Taul, C., Kolko, M., Stålhammar, G., Brautaset, R., Locri, F., Williams, P. A., et al. (2026) · Acta Neuropathologica Communications · doi:10.1186/s40478-026-02388-7
Immunological drivers of oxidative stress in glaucoma: implications for antioxidant therapy
Lin, B., Fan, W., & Li, D.-K. (2026) · Graefe s Archive for Clinical and Experimental Ophthalmology · doi:10.1007/s00417-026-07445-4
Assessing microglial phagocytosis of apoptotic neurons in vitro: a multimodal approach
Mukwaya, A., Yin, Z., Yarcusko, R., Baldwin, G., Uddin, M. N., Venkat, H., Xue, Y., Arnam, N. S. V., Kam, H., Chen, D. F., et al. (2026) · Frontiers in Neuroscience · doi:10.3389/fnins.2026.1813556
Self-citationLi, C., Song, R., & Yu, L. (2026) · Frontiers in Neurology · doi:10.3389/fneur.2026.1940010
Wenhua, Y., Wenjing, M., Yan, D., Fei, L., Chen, J., Xia, T., Guan, Y., Xin, L., Huang, Y., Guo, Y., et al. (2026) · Frontiers in Neurology · doi:10.3389/fneur.2026.1934307
Bagyinszky, E., & An, S. S. A. (2026) · Current Issues in Molecular Biology · doi:10.3390/cimb48101081
Kriukov, E., Mukwaya, A., Cullen, P., Kam, H. T., Baldwin, G., Malechka, V. V., Refaian, N., Bagaev, N., Labrecque, E., Vinjamuri, S., et al. (2026) · iScience · doi:10.1016/j.isci.2026.117232 · Cited by 4
Self-citation
Metadata
- Authors
- Margeta, M. A., Yin, Z., Madore, C., Pitts, K. M., Letcher, S. M., Tang, J., Jiang, S., Gauthier, C. D., Silveira, S. R., Schroeder, C. M., Lad, E. M., Proia, A. D., Tanzi, R. E., Holtzman, D. M., Krasemann, S., Chen, D. F., & Butovsky, O.
- Affiliations
- Brigham and Women's Hospital (US)
- Massachusetts Eye and Ear Infirmary (US)
- Duke Medical Center (US)
- Campbell University (US)
- Harvard University (US)
- Washington University in St. Louis (US)
- University Medical Center Hamburg-Eppendorf (DE)
- Corresponding author
- Butovsky, Oleg
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2022-09
- Volume
- 55
- Issue
- 9
- Pages
- 1627-1644.e7
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC9488669
- OpenAlex
- W4292055662
- Cited by
- 130
- References
- 104
- Citations by year
- 2026: 33 · 2025: 32 · 2024: 27 · 2023: 31 · 2022: 6
- FWCI
- 21.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 629 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Oskar-Bordeaux (Universite de Bordeaux) (submittedVersion)
- Funders
- BrightFocus Foundation (2020A016806)
- National Multiple Sclerosis Society (5092A1)
- National Institute of Neurological Disorders and Stroke (R01 NS088137)
- National Institute on Aging (R01 AG054672, R01 AG051812)
- American Glaucoma Society
- ALS Association (EY025913, EY025259)
- Cure Alzheimer's Fund
- NIH
- National Eye Institute (K08 EY030160, R01 EY027921, K12 EY016335)
- Research to Prevent Blindness
- National Health and Medical Research Council (RG180378)
- Topics
- Health Sciences › Medicine › Ophthalmology › Glaucoma and retinal disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- APOE ε4, glaucoma, retinal microglia, neurodegeneration, retinal ganglion cell death, galectin-3, intraocular pressure, microglial activation, neuroprotection, ApoE-deficient mice, glaucoma treatment
- MeSH terms
- Animals, Apolipoproteins E, Disease Models, Animal, Glaucoma, Humans, Microglia, Galectin 3, Mice, Apolipoprotein E4
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
