Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma

Margeta, Milica A.; Yin, Zhuoran; Madore, Charlotte; Pitts, Kristen M.; Letcher, Sophia M.; Tang, Jing; Jiang, Shiqin; Gauthier, Christian; Silveira, Sebastian R.; Schroeder, Caitlin M.; Cocce, Kimberly J.; Proia, Alan D.; Tanzi, Rudolph E.; Holtzman, David M.; Krasemann, Susanne; Chen, Dong F.; Butovsky, Oleg

doi:10.1016/j.immuni.2022.07.014

Cited by 57 publications

(52 citation statements)

References 100 publications

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“… 13 Recent work has shown that mice with global or microglia-specific deletion of Apoe are protected from RGC loss in glaucoma, demonstrating that this molecule acts cell-autonomously in microglia to drive disease progression. 19 , 21 Consistent with this role, APOE has previously been detected in both the aqueous humor (AH) and retinal tissue of human glaucoma samples. 12 , 13 Of note, although mice possess only one isoform of Apoe , in humans it is found as three distinct isoforms ( APOE2, APOE3 , and APOE4 ).…”

Section: Introductionmentioning

confidence: 69%

“… 13 – 16 Researchers have named this activated microglial state “MGnD,” 13 , 17 for microglia in neurodegeneration, or “DAM,” 14 for disease-associated microglia, and they have implicated it in a myriad of CNS degenerations. 15 , 18 Importantly, this microglial phenotype has also recently been described in mouse models of glaucoma 19 and photoreceptor degeneration. 20 …”

Section: Introductionmentioning

confidence: 78%

“… 23 – 25 We have recently used humanized mice with APOE3 and APOE4 alleles to demonstrate that APOE4 acts as a loss-of-function isoform, which preserves RGCs by impairing microglial activation in a manner similar to Apoe deletion. 19 This discovery may explain the protective effect of APOE4 in the human population.…”

Section: Introductionmentioning

confidence: 90%

“…Gal-3, a secreted, carbohydrate-binding lectin, has been identified as a critical downstream effector of APOE signaling in microglia, whose upregulation is abrogated in both APOE4 and Apoe knockout mice with glaucoma. 19 Interestingly, Gal-3 has been implicated in several other CNS neurodegenerations, such as Alzheimer's disease, 29 Huntington's disease, 30 multiple sclerosis, 31 and traumatic optic neuropathy, 32 as well as in systemic inflammatory conditions, including pulmonary fibrosis. 33 – 35 Targeting Gal-3 in mouse models of these diseases led to amelioration of anatomic and functional outcomes.…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, targeting Gal-3 both genetically and by intravitreal injection of a selective small molecule inhibitor resulted in robust protection of RGCs despite IOP elevation in a mouse model of glaucoma. 19 Therefore Gal-3 inhibition has the potential to become a powerful neuroprotective strategy for the treatment of this blinding disease.…”

Section: Introductionmentioning

confidence: 99%

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Neurodegeneration Markers Galectin-3 and Apolipoprotein E Are Elevated in the Aqueous Humor of Eyes With Glaucoma

Pitts

Neeson

Hall

et al. 2022

Trans. Vis. Sci. Tech.

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Purpose Galectin-3 (Gal-3) and apolipoprotein E (APOE) are markers of activated microglia in neurodegenerative diseases of the central nervous system, whose targeting is protective in mouse models of glaucoma. In this study, we examined levels of Gal-3 and APOE in human aqueous humor (AH) and defined their clinical associations with glaucoma. Methods We collected AH from 59 glaucoma patients and 15 controls at the start of planned ophthalmic surgery. Gal-3 and APOE levels were quantified by enzyme-linked immunosorbent assay. Total protein in AH was quantified by bicinchoninic acid assay. Significant associations between Gal-3, APOE, and clinical covariates were defined using univariate and multivariate linear regression models. Results Gal-3 and APOE levels were significantly elevated in the AH of glaucoma patients compared to controls ( P = 0.004 and P < 0.001, respectively). Gal-3 and APOE were positively correlated across the entire cohort (r = 0.65, P = 6.2E-9). No association was observed between Gal-3 and total protein or APOE and total protein ( P = 0.35 and P = 0.50, respectively), indicating that their levels were not increased in glaucomatous AH due to nonspecific protein accumulation. Multivariate linear regression modeling revealed significant associations between Gal-3 and maximum recorded intraocular pressure ( P = 0.009) and between APOE and number of past ophthalmic surgeries ( P = 0.031). Conclusions We demonstrate that Gal-3 and APOE are significantly elevated in the AH of eyes with glaucoma and are associated with a history of poorly controlled disease. Translational Relevance Gal-3 and APOE in AH may inform clinical decision-making as quantifiable readouts of microglial activation in eyes with glaucoma.

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Section: Introductionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Neurodegeneration Markers Galectin-3 and Apolipoprotein E Are Elevated in the Aqueous Humor of Eyes With Glaucoma

Pitts

Neeson

Hall

et al. 2022

Trans. Vis. Sci. Tech.

Self Cite

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Long‐Term Monitoring of ApoE4 within Aqueous Humor Using Intraocular Lenses Containing Target‐Responsive Inverse Opal Hydrogel

Lee,

Lim,

Shin

et al. 2024

Small Structures

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Neurodegenerative diseases, including Alzheimer's disease (AD), pose significant challenges to global healthcare because of their irreversible postsymptomatic progression. Conventional radiographic techniques have limitations in early detection, owing to the time lapse between symptom recognition by individuals and precise inspection using medical instruments. Current research explores ophthalmic approaches to address this gap, investigating the physiological link between ocular health and brain diseases. Intraocular lenses (IOLs), widely used in cataract and refractive surgeries, provide a safe and minimally invasive platform for the continuous monitoring of neurodegenerative disease biomarkers, including those associated with AD. By integrating biomolecule‐responsive sensors with IOLs, it becomes feasible to achieve early diagnosis and long‐term, noninvasive monitoring postimplantation. Herein, a fluorescently labeled inverse opal hydrogel (FIOH) is merged with IOLs for ApoE4 detection, a key risk factor for AD. The permeability and inherent photonic properties of FIOH facilitate the cumulative enhancement of the fluorescence signal. In a simulation of the aqueous humor circulation, the detection limit for ApoE4 is determined to be 0.1 nM. Therefore, FIOH‐integrated IOLs hold promise not only for early detection but also for providing a reliable platform for the continuous, noninvasive monitoring of neurodegenerative diseases after the initial, minimally invasive implantation.

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Proteomic and Cytokine Profiling in Plasma from Patients with Normal-Tension Glaucoma and Ocular Hypertension

Langbøl,

Saruhanian,

Saruhanian

et al. 2024

Cell Mol Neurobiol

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Primary open-angle glaucoma (POAG) is subdivided depending on eye pressure. Patients with normal-tension glaucoma (NTG) have never had high intraocular pressure (IOP) measured while patients with ocular hypertension (OHT) have high eye pressure but no signs of glaucoma. Although IOP is considered to be a risk factor for all glaucoma patients, it is reasonable to assume that other risk factors such as inflammation play a role. We aimed to characterize the proteome and cytokine profile during hypoxia in plasma from patients with NTG (n = 10), OHT (n = 10), and controls (n = 10). Participants were exposed to hypoxia for two hours, followed by 30 min of normoxia. Samples were taken before (“baseline”), during (“hypoxia”), and after hypoxia (“recovery”). Proteomics based on liquid chromatography coupled with mass spectrometry (LC–MS) was performed. Cytokines were measured by Luminex assays. Bioinformatic analyses indicated the involvement of complement and coagulation cascades in NTG and OHT. Regulation of high-density lipoprotein 3 (HDL3) apolipoproteins suggested that changes in cholesterol metabolism are related to OHT. Hypoxia decreased the level of tumor necrosis factor-α (TNF-α) in OHT patients compared to controls. Circulating levels of interleukin-1β (IL-1β) and C-reactive protein (CRP) were decreased in NTG patients compared to controls during hypoxia. After recovery, plasma interleukin-6 (IL-6) was upregulated in patients with NTG and OHT. Current results indicate an enhanced systemic immune response in patients with NTG and OHT, which correlates with pathogenic events in glaucoma. Apolipoproteins may have anti-inflammatory effects, enabling OHT patients to withstand inflammation and development of glaucoma despite high IOP. Graphical Abstract

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Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma

Cited by 57 publications

References 100 publications

Neurodegeneration Markers Galectin-3 and Apolipoprotein E Are Elevated in the Aqueous Humor of Eyes With Glaucoma

Neurodegeneration Markers Galectin-3 and Apolipoprotein E Are Elevated in the Aqueous Humor of Eyes With Glaucoma

Long‐Term Monitoring of ApoE4 within Aqueous Humor Using Intraocular Lenses Containing Target‐Responsive Inverse Opal Hydrogel

Proteomic and Cytokine Profiling in Plasma from Patients with Normal-Tension Glaucoma and Ocular Hypertension

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