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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.
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“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]
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“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]
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“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]
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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
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