Targeting Microglia to Treat Degenerative Eye Diseases

Wang, Sean K.; Cepko, Constance L.

doi:10.3389/fimmu.2022.843558

Cited by 30 publications

(27 citation statements)

References 169 publications

(231 reference statements)

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“…Paradoxically, the APOE4 genotype protects against macular degeneration onset, whereas APOE2 carriers presented an earlier disease onset [ 773 ]. The implications of microglial cells in degenerative eye diseases such as primary open-angle glaucoma and age-related macular degeneration have been previously described, and animal studies suggest targeting microglial cells as a potential treatment for eye disorders [ 774 ]. Ocular disorders present some common hallmarks of neurodegenerative diseases and CNS pathologies extensively discussed by other authors [ 775 ], such as the connection between apoE metabolism and retinal inflammation linked to age-related macular degeneration [ 776 ].…”

Section: Discussionmentioning

confidence: 99%

APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases

Fernández-Calle

Konings

Frontiñán-Rubio

et al. 2022

Mol Neurodegeneration

100

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ApoE is the major lipid and cholesterol carrier in the CNS. There are three major human polymorphisms, apoE2, apoE3, and apoE4, and the genetic expression of APOE4 is one of the most influential risk factors for the development of late-onset Alzheimer's disease (AD). Neuroinflammation has become the third hallmark of AD, together with Amyloid-β plaques and neurofibrillary tangles of hyperphosphorylated aggregated tau protein. This review aims to broadly and extensively describe the differential aspects concerning apoE. Starting from the evolution of apoE to how APOE's single-nucleotide polymorphisms affect its structure, function, and involvement during health and disease. This review reflects on how APOE's polymorphisms impact critical aspects of AD pathology, such as the neuroinflammatory response, particularly the effect of APOE on astrocytic and microglial function and microglial dynamics, synaptic function, amyloid-β load, tau pathology, autophagy, and cell–cell communication. We discuss influential factors affecting AD pathology combined with the APOE genotype, such as sex, age, diet, physical exercise, current therapies and clinical trials in the AD field. The impact of the APOE genotype in other neurodegenerative diseases characterized by overt inflammation, e.g., alpha- synucleinopathies and Parkinson's disease, traumatic brain injury, stroke, amyotrophic lateral sclerosis, and multiple sclerosis, is also addressed. Therefore, this review gathers the most relevant findings related to the APOE genotype up to date and its implications on AD and CNS pathologies to provide a deeper understanding of the knowledge in the APOE field.

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Section: Discussionmentioning

confidence: 99%

APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases

Fernández-Calle

Konings

Frontiñán-Rubio

et al. 2022

Mol Neurodegeneration

100

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“…To clarify the role of microglia in DR initiation and progression, we utilized two models to deplete microglia, a spatially and temporally controlled conditional model using CX3CR1 CreER :R26 iDTR mice, and a pharmacological model, PLX-5622, in CX3CR1 -WT mice [ 9 , 10 ]. Analysis of brain, spinal cord and retinal CX3CR1 CreER :R26 iDTR tissues revealed CNS regional differences in the extent of microglial depletion, with greater susceptibility in the retina following acute DTx treatment.…”

Section: Discussionmentioning

confidence: 99%

“…To clarify the contribution of retinal microglia to disease progression we sought to transiently deplete and repopulate microglia using a genetic approach, CX3CR1 CreER :R26 iDTR transgenic mice, and a pharmacological approach via CSF-1R antagonist (PLX-5622) in a streptozotocin-induced diabetic model [ 9 , 10 ]. Neither model resulted in complete elimination of the Iba1 + retinal microglia cells, but lead to significant reduction in the overall density of Iba1 + cells.…”

Section: Introductionmentioning

confidence: 99%

Models of microglia depletion and replenishment elicit protective effects to alleviate vascular and neuronal damage in the diabetic murine retina

Church

Rodriguez

Vanegas

et al. 2022

J Neuroinflammation

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Microglia, the resident phagocytes of the retina, are believed to influence the development of retinopathy, but their exact contributions to vascular integrity and neuronal loss are unknown. Therefore, utilizing two models of microglia depletion, we aimed to deplete and repopulate microglia to clarify the contribution of microglia to neuronal loss and vascular damage in the diabetic retina in an STZ-induced model of hyperglycemia. Here, we report that 2 weeks exposure to diphtheria toxin (DTx) in diabetic CX3CR1CreER:R26iDTR transgenic mice induced a 62% increase in Iba1+ microglia associated with an increase in TUJ1+ axonal density and prevention of NeuN+RBPMS+ neuronal loss. Conversely, diabetic PBS controls exhibited robust TUJ1+ axonal and NeuN+RBPMS+ neuronal loss compared to non-diabetic controls. A 2-week recovery period from DTx was associated with a 40% reduction in angiogenesis and an 85% reduction in fibrinogen deposition into the diabetic retina in comparison to diabetic PBS-treated controls. Analysis of microglia morphology and marker expression revealed that following a 2-week recovery period microglia displayed a P2RY12+Ly6C– phenotype and high transformation index (TI) values complimented by a ramified-surveillant morphology closely resembling non-diabetic controls. In contrast, diabetic PBS-treated control mice displayed P2RY12+Ly6C+ microglia, with a 50% reduction in TI values with an amoeboid morphology. To validate these observations were due to microglia depletion, we used PLX-5622 to assess vascular and neuronal damage in the retinas of diabetic mice. Confocal microscopy revealed that PLX-5622 also induced an increase in TUJ1+ axonal density and prevented fibrinogen extravasation into the diabetic retina. mRNAseq gene expression analysis in retinal isolates revealed that PLX-5622-induced microglia depletion and repopulation induced a downregulation in genes associated with microglial activation and phagocytosis, B2m, Cx3cr1, and Trem2, and complement-associated synaptic pruning, C1qa, C1qb, and C1qc. Although the levels of microglia depletion induced with DTx in the CX3CR1CreER:R26iDTR model and those induced with the CSF-1R antagonists are distinct, our results suggest that microglia depletion and replenishment is neuroprotective by inducing the proliferation of a homeostatic microglia pool that supports neuronal and vascular integrity.

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“…The consumption of retinal microglia leads to delayed retinal vascular development [ 10 ]. It is particularly worth mentioning that in the ischemic retina, microglia accumulated in the ischemia and NV regions and were considered to be the driving force of the pathological process [ 11 , 12 ]. After being activated under the circumstance of ischemic insult, microglia secreted proinflammatory and anti-inflammatory cytokines and reversed the cellular microenvironment by clearing neurons and exclusive vessel units [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Distinguished Functions of Microglia in the Two Stages of Oxygen-Induced Retinopathy: A Novel Target in the Treatment of Ischemic Retinopathy

Zhou

Jing

Niu

et al. 2022

Life

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Microglia is the resident immune cell in the retina, playing the role of immune surveillance in a traditional concept. With the heated focus on the mechanisms of microglia in pathological conditions, more and more functions of microglia have been discovered. Although the regulating role of microglia has been explored in ischemic retinopathy, little is known about its mechanisms in the different stages of the pathological process. Here, we removed microglia in the oxygen-induced retinopathy model by PLX5622 and revealed that the removal of activated microglia reduced pathological angiogenesis in the early stage after ischemic insult and alleviated the over-apoptosis of photoreceptors in the vessel remodeling phase. Our results indicated that microglia might play distinguished functions in the angiogenic and remodeling stages, and that the inhibition of microglia might be a promising target in the future treatment of ischemic retinopathy.

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Targeting Microglia to Treat Degenerative Eye Diseases

Cited by 30 publications

References 169 publications

APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases

APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases

Models of microglia depletion and replenishment elicit protective effects to alleviate vascular and neuronal damage in the diabetic murine retina

Distinguished Functions of Microglia in the Two Stages of Oxygen-Induced Retinopathy: A Novel Target in the Treatment of Ischemic Retinopathy

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