Glia-Mediated Retinal Neuroinflammation as a Biomarker in Alzheimer's Disease

Madeira, Maria; Ambrósio, António Francisco; Santiago, Ana Raquel

doi:10.1159/000440887

Cited by 8 publications

(14 citation statements)

References 97 publications

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“…In AD, microglial activation in the brain has been demonstrated, indicating that a neuroinflammatory process occurs in this disease [5,35]. In a normal adult nervous system, microglia are found in a quiescent state characterized by a ramified morphology [36].…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, during disease progression, the anti-inflammatory profile changed to a pro-inflammatory one, allowing potentially neurotoxic genes to be overexpressed (iNOS, IL-1β) [27]. Therefore, chronic activation of the microglia, with a constant release of proinflammatory factors, could cause a decrease in both Aβ phagocytosis and neurotoxicity, which would lead to neuronal death [35].…”

Section: Discussionmentioning

confidence: 99%

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Microglial Activation in the Retina of a Triple-Transgenic Alzheimer’s Disease Mouse Model (3xTg-AD)

Salobrar‐García

Rodrigues‐Neves

Ramírez

et al. 2020

IJMS

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Alzheimer’s disease (AD) is the most common type of dementia in the world. The main biomarkers associated with AD are protein amyloid-β (Aβ) plaques and protein tau neurofibrillary tangles, which are responsible for brain neuroinflammation mediated by microglial cells. Increasing evidence has shown that the retina can also be affected in AD, presenting some molecular and cellular changes in the brain, such as microglia activation. However, there are only a few studies assessing such changes in the retinal microglia in animal models of AD. These studies use retinal sections, which have some limitations. In this study, we performed, for the first time in a triple-transgenic AD mouse model (3xTg-AD), a quantitative morphometric analysis of microglia activation (using the anti-Iba-1 antibody) in retinal whole-mounts, allowing visualization of the entire microglial cell, as well as its localization along the extension of the retina in different layers. Compared to age-matched animals, the retina of 3xTg-AD mice presents a higher number of microglial cells and a thicker microglial cell body area. Moreover, the microglia migrate, reorient, and retract their processes, changing their localization from a parallel to a perpendicular position relative to the retinal surface. These findings demonstrate clear microglia remodeling in the retina of 3xTg-AD mice.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Microglial Activation in the Retina of a Triple-Transgenic Alzheimer’s Disease Mouse Model (3xTg-AD)

Salobrar‐García

Rodrigues‐Neves

Ramírez

et al. 2020

IJMS

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“…Retinal pathology has recently been intensively discussed in the context of Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis (39, 40). Furthermore, unprecedented breakthroughs are possible in the context of pathologies such as genetic vasculature diseases and diabetes type I (41, 42), which are associated with changes of the retinal vasculature, including main blood vessels and capillaries.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal Intravital Imaging of the Retina Reveals Long-term Dynamics of Immune Infiltration and Its Effects on the Glial Network in Experimental Autoimmune Uveoretinitis, without Evident Signs of Neuronal Dysfunction in the Ganglion Cell Layer

et al. 2016

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A hallmark of autoimmune retinal inflammation is the infiltration of the retina with cells of the innate and adaptive immune system, leading to detachment of the retinal layers and even to complete loss of the retinal photoreceptor layer. As the only optical system in the organism, the eye enables non-invasive longitudinal imaging studies of these local autoimmune processes and of their effects on the target tissue. Moreover, as a window to the central nervous system (CNS), the eye also reflects general neuroinflammatory processes taking place at various sites within the CNS. Histological studies in murine neuroinflammatory models, such as experimental autoimmune uveoretinitis (EAU) and experimental autoimmune encephalomyelitis, indicate that immune infiltration is initialized by effector CD4+ T cells, with the innate compartment (neutrophils, macrophages, and monocytes) contributing crucially to tissue degeneration that occurs at later phases of the disease. However, how the immune attack is orchestrated by various immune cell subsets in the retina and how the latter interact with the target tissue under in vivo conditions is still poorly understood. Our study addresses this gap with a novel approach for intravital two-photon microscopy, which enabled us to repeatedly track CD4+ T cells and LysM phagocytes during the entire course of EAU and to identify a specific radial infiltration pattern of these cells within the inflamed retina, starting from the optic nerve head. In contrast, highly motile CX3CR1+ cells display an opposite radial motility pattern, toward the optic nerve head. These inflammatory processes induce modifications of the microglial network toward an activated morphology, especially around the optic nerve head and main retinal blood vessels, but do not affect the neurons within the ganglion cell layer. Thanks to the new technology, non-invasive correlation of clinical scores of CNS-related pathologies with immune infiltrate behavior and subsequent tissue dysfunction is now possible. Hence, the new approach paves the way for deeper insights into the pathology of neuroinflammatory processes on a cellular basis, over the entire disease course.

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“…AD is a progressive neurodegenerative disease characterized by a decline in cognitive function and memory resulting from synapse and cell loss, accompanied by a strong neuroinflammatory response. It accounts for 60–80% of dementia cases, and is the leading cause of these in the population over 60 years old 2 …”

Section: Alzheimer's Diseasementioning

confidence: 99%

“…It has been shown that both microglia and astrocytes, not neurons, are the main source of N-terminally truncated Aβ peptides that can be found in amyloid deposits 2 . Aβ plaques stimulate the factors and proteins that induce the production of inflammatory cytokines and chemokines.…”

Section: Neurodegeneration Glial Response and Alzheimer'smentioning

confidence: 99%

Retinal glial changes in Alzheimer's disease – A review

Fernández‐Albarral

Salobrar‐García

Martínez-Páramo

et al. 2019

Journal of Optometry

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Alzheimer's disease (AD) is a neurodegenerative dementia characterized by the deposition of extracellular β-amyloid (Aβ) plaques and the presence of neurofibrillary tangles. Until now, the techniques used to analyze these deposits have been difficult to access, invasive, and expensive. This leads us to consider new access routes to the central nervous system (CNS), allowing us to diagnose the disease before the first symptoms appear. Recent studies have shown that microglial and macroglial cell activation could play a role in the development of this disease. Glial cells in the CNS can respond to various damages, such as neurodegenerative pathologies, with morphological and functional changes. These changes are a common feature in neurodegenerative diseases, including AD. The retina is considered an extension of the CNS and has a population of glial cells similar to that of the CNS. When glial cells are activated, various molecules are released and changes in glial cell expression occur, which can be indicators of neuronal damage. The objective of this review is to compile the most relevant findings in the last 10 years relating to alterations in the eye in AD, and the role that glial cells play in the degenerative process in the retina in the context of neurodegeneration.

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Glia-Mediated Retinal Neuroinflammation as a Biomarker in Alzheimer's Disease

Cited by 8 publications

References 97 publications

Microglial Activation in the Retina of a Triple-Transgenic Alzheimer’s Disease Mouse Model (3xTg-AD)

Microglial Activation in the Retina of a Triple-Transgenic Alzheimer’s Disease Mouse Model (3xTg-AD)

Longitudinal Intravital Imaging of the Retina Reveals Long-term Dynamics of Immune Infiltration and Its Effects on the Glial Network in Experimental Autoimmune Uveoretinitis, without Evident Signs of Neuronal Dysfunction in the Ganglion Cell Layer

Retinal glial changes in Alzheimer's disease – A review

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