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Retinal Neurodegenerative Diseases: Molecular Targets Driving Neuroinflammation and Neuroprotection
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Retinal Neurodegenerative Diseases: Molecular Targets Driving Neuroinflammation and Neuroprotection

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 53920

Special Issue Editors

Dr. Ana Raquel Santiago

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Guest Editor
Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Interests: retinal diseases; neuroprotection; neurodegeneration; neuroinflammation; neuro-immune interactions; drug delivery systems; intercellular communication; extracellular vesicles
Special Issues, Collections and Topics in MDPI journals
Dr. Raquel Boia

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Guest Editor
Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Interests: retinal diseases; retinal ganglion cells; neuroprotection; neurodegeneration; neuroinflammation; drug delivery systems

Special Issue Information

Dear Colleagues,

Retinal neurodegenerative diseases are among the major causes of blindness worldwide. Glaucoma, diabetic retinopathy, and age-related macular degeneration (AMD) are chronic diseases affecting more than 150 million people worldwide. Despite their different etiologies, chronic neuroinflammation is a common feature that correlates with neurodegeneration. Several cells, like microglia, astrocytes, and immune cells from the periphery and endothelial cells, orchestrate an inflammatory response that drive neurodegeneration. The inflammatory signals occur early and precede neurodegeneration, suggesting that strategies targeting the control of inflammation could provide therapeutic benefits for the treatment of retinal diseases. Several molecular targets and strategies have been proposed to afford protection to the retina, either by acting directly on the affected cells or by controlling inflammation.

A better knowledge of the molecular and cellular mechanisms behind neuronal loss will contribute to the clarification of disease etiology, and might open avenues for potential therapeutic interventions.

This Special Issue is focused on the molecular mechanisms of retinal neurodegenerative diseases, including the contribution of neuroinflammation to pathology. Manuscripts presenting molecular targets for therapeutic intervention and new therapeutic strategies for retinal neurodegenerative diseases are also welcome.

You are warmly invited to submit original research, mini- and full reviews, short communications, as well as perspectives addressing any aspect related to the current topic.

Dr. Ana Raquel Santiago
Dr. Raquel Boia
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Retinal neurodegenerative diseases
  • Retinal neuronal degeneration
  • Glia-mediated neurodegeneration
  • Neuroprotection
  • Axonal regeneration
  • Drug delivery systems
  • Therapeutic strategies
  • Molecular targets

Published Papers (15 papers)

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Research

Jump to: Review

18 pages, 2750 KiB  
Article
Pharmacological Inhibition of Spermine Oxidase Suppresses Excitotoxicity Induced Neuroinflammation in Mouse Retina
by Moaddey Alfarhan, Fang Liu, Shengshuai Shan, Prahalathan Pichavaram, Payaningal R. Somanath and S. Priya Narayanan
Int. J. Mol. Sci. 2022, 23(4), 2133; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042133 - 15 Feb 2022
Cited by 12 | Viewed by 2183
Abstract
Polyamine oxidation plays a major role in neurodegenerative diseases. Previous studies from our laboratory demonstrated that spermine oxidase (SMOX, a member of the polyamine oxidase family) inhibition using MDL 72527 reduced neurodegeneration in models of retinal excitotoxicity and diabetic retinopathy. However, the mechanisms [...] Read more.
Polyamine oxidation plays a major role in neurodegenerative diseases. Previous studies from our laboratory demonstrated that spermine oxidase (SMOX, a member of the polyamine oxidase family) inhibition using MDL 72527 reduced neurodegeneration in models of retinal excitotoxicity and diabetic retinopathy. However, the mechanisms behind the neuroprotection offered by SMOX inhibition are not completely studied. Utilizing the experimental model of retinal excitotoxicity, the present study determined the impact of SMOX blockade in retinal neuroinflammation. Our results demonstrated upregulation in the number of cells positive for Iba-1 (ionized calcium-binding adaptor molecule 1), CD (Cluster Differentiation) 68, and CD16/32 in excitotoxicity-induced retinas, while MDL 72527 treatment reduced these changes, along with increases in the number of cells positive for Arginase1 and CD206. When retinal excitotoxicity upregulated several pro-inflammatory genes, MDL 72527 treatment reduced many of them and increased anti-inflammatory genes. Furthermore, SMOX inhibition upregulated antioxidant signaling (indicated by elevated Nrf2 and HO-1 levels) and reduced protein-conjugated acrolein in excitotoxic retinas. In vitro studies using C8-B4 cells showed changes in cellular morphology and increased reactive oxygen species formation in response to acrolein (a product of SMOX activity) treatment. Overall, our findings indicate that the inhibition SMOX pathway reduced neuroinflammation and upregulated antioxidant signaling in the retina. Full article
(This article belongs to the Special Issue Retinal Neurodegenerative Diseases: Molecular Targets Driving Neuroinflammation and Neuroprotection)
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23 pages, 6917 KiB  
Article
Myelinosome Organelles in the Retina of R6/1 Huntington Disease (HD) Mice: Ubiquitous Distribution and Possible Role in Disease Spreading
by Marina G. Yefimova, Emile Béré, Anne Cantereau-Becq, Annie-Claire Meunier-Balandre, Bruno Merceron, Agnès Burel, Karine Merienne, Célia Ravel, Frédéric Becq and Nicolas Bourmeyster
Int. J. Mol. Sci. 2021, 22(23), 12771; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312771 - 25 Nov 2021
Cited by 4 | Viewed by 2324
Abstract
Visual deficit is one of the complications of Huntington disease (HD), a fatal neurological disorder caused by CAG trinucleotide expansions in the Huntingtin gene, leading to the production of mutant Huntingtin (mHTT) protein. Transgenic HD R6/1 mice expressing human HTT exon1 with 115 [...] Read more.
Visual deficit is one of the complications of Huntington disease (HD), a fatal neurological disorder caused by CAG trinucleotide expansions in the Huntingtin gene, leading to the production of mutant Huntingtin (mHTT) protein. Transgenic HD R6/1 mice expressing human HTT exon1 with 115 CAG repeats recapitulate major features of the human pathology and exhibit a degeneration of the retina. Our aim was to gain insight into the ultrastructure of the pathological HD R6/1 retina by electron microscopy (EM). We show that the HD R6/1 retina is enriched with unusual organelles myelinosomes, produced by retinal neurons and glia. Myelinosomes are present in all nuclear and plexiform layers, in the synaptic terminals of photoreceptors, in the processes of retinal neurons and glial cells, and in the subretinal space. In vitro study shows that myelinosomes secreted by human retinal glial Müller MIO-M1 cells transfected with EGFP-mHTT-exon1 carry EGFP-mHTT-exon1 protein, as revealed by immuno-EM and Western-blotting. Myelinosomes loaded with mHTT-exon1 are incorporated by naive neuronal/neuroblastoma SH-SY5Y cells. This results in the emergence of mHTT-exon1 in recipient cells. This process is blocked by membrane fusion inhibitor MDL 28170. Conclusion: Incorporation of myelinosomes carrying mHTT-exon1 in recipient cells may contribute to HD spreading in the retina. Exploring ocular fluids for myelinosome presence could bring an additional biomarker for HD diagnostics. Full article
(This article belongs to the Special Issue Retinal Neurodegenerative Diseases: Molecular Targets Driving Neuroinflammation and Neuroprotection)
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12 pages, 10009 KiB  
Article
The Anti-Inflammatory Effect of Hydrogen Gas Inhalation and Its Influence on Laser-Induced Choroidal Neovascularization in a Mouse Model of Neovascular Age-Related Macular Degeneration
by I-Chia Liang, Wen-Chin Ko, Yu-Jou Hsu, Yi-Ru Lin, Yun-Hsiang Chang, Xv-Hui Zong, Pei-Chen Lai, Der-Chen Chang and Chi-Feng Hung
Int. J. Mol. Sci. 2021, 22(21), 12049; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222112049 - 07 Nov 2021
Cited by 7 | Viewed by 3546
Abstract
Background: Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly. Choroidal neovascularization (CNV) is the major pathologic feature of neovascular AMD. Oxidative damages and the ensuing chronic inflammation are representative of trigger events. Hydrogen gas (H2) has [...] Read more.
Background: Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly. Choroidal neovascularization (CNV) is the major pathologic feature of neovascular AMD. Oxidative damages and the ensuing chronic inflammation are representative of trigger events. Hydrogen gas (H2) has been demonstrated as an antioxidant and plays a role in the regulation of oxidative stress and inflammation. This experiment aimed to investigate the influence of H2 inhalation on a mouse model of CNV. Methods: Laser was used to induce CNV formation. C57BL/6J mice were divided into five groups: the control group; the laser-only group; and the 2 h, 5 h, and 2.5 h/2.5 h groups that received laser and H2 inhalation (21% oxygen, 42% hydrogen, and 37% nitrogen mixture) for 2 h, 5 h, and 2.5 h twice every day, respectively. Results: The severity of CNV leakage on fluorescence angiography showed a significant decrease in the H2 inhalation groups. The mRNA expression of hypoxia-inducible factor 1 alpha and its immediate downstream target vascular endothelial growth factor (VEGF) showed significant elevation after laser, and this elevation was suppressed in the H2 inhalation groups in an inhalation period length-related manner. The mRNA expression of cytokines, including tumor necrosis factor alpha and interlukin-6, also represented similar results. Conclusion: H2 inhalation could alleviate CNV leakage in a laser-induced mouse CNV model, and the potential mechanism might be related to the suppression of the inflammatory process and VEGF-driven CNV formation. Full article
(This article belongs to the Special Issue Retinal Neurodegenerative Diseases: Molecular Targets Driving Neuroinflammation and Neuroprotection)
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22 pages, 6641 KiB  
Article
Polyphenol Metabolite Pyrogallol-O-Sulfate Decreases Microglial Activation and VEGF in Retinal Pigment Epithelium Cells and Diabetic Mouse Retina
by Daniela F. Santos, Mariana Pais, Cláudia N. Santos and Gabriela A. Silva
Int. J. Mol. Sci. 2021, 22(21), 11402; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111402 - 22 Oct 2021
Cited by 3 | Viewed by 2479
Abstract
(Poly)phenol-derived metabolites are small molecules resulting from (poly)phenol metabolization after ingestion that can be found in circulation. In the last decade, studies on the impact of (poly)phenol properties in health and cellular metabolism accumulated evidence that (poly)phenols are beneficial against human diseases. Diabetic [...] Read more.
(Poly)phenol-derived metabolites are small molecules resulting from (poly)phenol metabolization after ingestion that can be found in circulation. In the last decade, studies on the impact of (poly)phenol properties in health and cellular metabolism accumulated evidence that (poly)phenols are beneficial against human diseases. Diabetic retinopathy (DR) is characterized by inflammation and neovascularization and targeting these is of therapeutic interest. We aimed to study the effect of pyrogallol-O-sulfate (Pyr-s) metabolite in the expression of proteins involved in retinal glial activation, neovascularization, and glucose transport. The expression of PEDF, VEGF, and GLUT-1 were analyzed upon pyrogallol-O-sulfate treatment in RPE cells under high glucose and hypoxia. To test its effect on a diabetic mouse model, Ins2Akita mice were subjected to a single intraocular injection of the metabolite and the expression of PEDF, VEGF, GLUT-1, Iba1, or GFAP measured in the neural retina and/or retinal pigment epithelium (RPE), two weeks after treatment. We observed a significant decrease in the expression of pro-angiogenic VEGF in RPE cells. Moreover, pyrogallol-O-sulfate significantly decreased the expression of microglial marker Iba1 in the diabetic retina at different stages of disease progression. These results highlight the potential pyrogallol-O-sulfate metabolite as a preventive approach towards DR progression, targeting molecules involved in both inflammation and neovascularization. Full article
(This article belongs to the Special Issue Retinal Neurodegenerative Diseases: Molecular Targets Driving Neuroinflammation and Neuroprotection)
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16 pages, 2816 KiB  
Article
Involvement of Oxidative and Endoplasmic Reticulum Stress in RDH12-Related Retinopathies
by Hajrah Sarkar, Maria Toms and Mariya Moosajee
Int. J. Mol. Sci. 2021, 22(16), 8863; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168863 - 18 Aug 2021
Cited by 8 | Viewed by 2878
Abstract
Retinol dehydrogenase 12 (RDH12) is expressed in photoreceptor inner segments and catalyses the reduction of all-trans retinal (atRAL) to all-trans retinol (atROL), as part of the visual cycle. Mutations in RDH12 are primarily associated with autosomal recessive Leber congenital amaurosis. To further our [...] Read more.
Retinol dehydrogenase 12 (RDH12) is expressed in photoreceptor inner segments and catalyses the reduction of all-trans retinal (atRAL) to all-trans retinol (atROL), as part of the visual cycle. Mutations in RDH12 are primarily associated with autosomal recessive Leber congenital amaurosis. To further our understanding of the disease mechanisms, HEK-293 cell lines expressing wildtype (WT) and mutant RDH12 were created. The WT cells afforded protection from atRAL-induced toxicity and oxidative stress. Mutant RDH12 cells displayed reduced protein expression and activity, with an inability to protect cells from atRAL toxicity, inducing oxidative and endoplasmic reticulum (ER) stress, with upregulation of sXBP1, CHOP, and ATF4. Pregabalin, a retinal scavenger, attenuated atRAL-induced ER stress in the mutant RDH12 cell lines. A zebrafish rdh12 mutant model (rdh12u533 c.17_23del; p.(Val6AlafsTer5)) was generated through CRISPR-Cas9 gene editing. Mutant fish showed disrupted phagocytosis through transmission electron microscopy, with increased phagosome size at 12 months post-fertilisation. Rhodopsin mislocalisation and reduced expression of atg12 and sod2 indicated early signs of a rod-predominant degeneration. A lack of functional RDH12 results in ER and oxidative stress representing key pathways to be targeted for potential therapeutics. Full article
(This article belongs to the Special Issue Retinal Neurodegenerative Diseases: Molecular Targets Driving Neuroinflammation and Neuroprotection)
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19 pages, 12474 KiB  
Article
Axonal Injuries Cast Long Shadows: Long Term Glial Activation in Injured and Contralateral Retinas after Unilateral Axotomy
by María José González-Riquelme, Caridad Galindo-Romero, Fernando Lucas-Ruiz, Marina Martínez-Carmona, Kristy T. Rodríguez-Ramírez, José María Cabrera-Maqueda, María Norte-Muñoz, Manuel Vidal-Sanz and Marta Agudo-Barriuso
Int. J. Mol. Sci. 2021, 22(16), 8517; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168517 - 07 Aug 2021
Cited by 13 | Viewed by 2204
Abstract
Background: To analyze the course of microglial and macroglial activation in injured and contralateral retinas after unilateral optic nerve crush (ONC). Methods: The left optic nerve of adult pigmented C57Bl/6 female mice was intraorbitally crushed and injured, and contralateral retinas were analyzed from [...] Read more.
Background: To analyze the course of microglial and macroglial activation in injured and contralateral retinas after unilateral optic nerve crush (ONC). Methods: The left optic nerve of adult pigmented C57Bl/6 female mice was intraorbitally crushed and injured, and contralateral retinas were analyzed from 1 to 45 days post-lesion (dpl) in cross-sections and flat mounts. As controls, intact retinas were studied. Iba1+ microglial cells (MCs), activated phagocytic CD68+MCs and M2 CD206+MCs were quantified. Macroglial cell changes were analyzed by GFAP and vimentin signal intensity. Results: After ONC, MC density increased significantly from 5 to 21 dpl in the inner layers of injured retinas, remaining within intact values in the contralateral ones. However, in both retinas there was a significant and long-lasting increase of CD68+MCs. Constitutive CD206+MCs were rare and mostly found in the ciliary body and around the optic-nerve head. While in the injured retinas their number increased in the retina and ciliary body, in the contralateral retinas decreased. Astrocytes and Müller cells transiently hypertrophied in the injured retinas and to a lesser extent in the contralateral ones. Conclusions: Unilateral ONC triggers a bilateral and persistent activation of MCs and an opposed response of M2 MCs between both retinas. Macroglial hypertrophy is transient. Full article
(This article belongs to the Special Issue Retinal Neurodegenerative Diseases: Molecular Targets Driving Neuroinflammation and Neuroprotection)
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20 pages, 7963 KiB  
Article
Fibroblast Growth Factor Type 1 Ameliorates High-Glucose-Induced Oxidative Stress and Neuroinflammation in Retinal Pigment Epithelial Cells and a Streptozotocin-Induced Diabetic Rat Model
by Hsin-Wei Huang, Chung-May Yang and Chang-Hao Yang
Int. J. Mol. Sci. 2021, 22(13), 7233; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22137233 - 05 Jul 2021
Cited by 12 | Viewed by 3021
Abstract
Diabetic retinopathy (DR) is a common complication of diabetes that causes severe visual impairment globally. The pathogenesis of DR is related to oxidative stress and chronic inflammation. The fibroblast growth factor type 1 (FGF-1) mitogen plays crucial roles in cell function, development, and [...] Read more.
Diabetic retinopathy (DR) is a common complication of diabetes that causes severe visual impairment globally. The pathogenesis of DR is related to oxidative stress and chronic inflammation. The fibroblast growth factor type 1 (FGF-1) mitogen plays crucial roles in cell function, development, and metabolism. FGF-1 is involved in blood sugar regulation and exerts beneficial antioxidative and anti-inflammatory effects on various organ systems. This study investigated the antioxidative and anti-inflammatory neuroprotective effects of FGF-1 on high-glucose-induced retinal damage. The results revealed that FGF-1 treatment significantly reversed the harmful effects of oxidative stress and inflammatory mediators in retinal tissue in a streptozotocin-induced diabetic rat model. These protective effects were also observed in the in vitro model of retinal ARPE-19 cells exposed to a high-glucose condition. We demonstrated that FGF-1 attenuated p38 mitogen-activated protein kinase and nuclear factor-κB pathway activation under the high-glucose condition. Our results indicated that FGF-1 could effectively prevent retinal injury in diabetes. The findings of this study could be used to develop novel treatments for DR that aim to reduce the cascade of oxidative stress and inflammatory signals in neuroretinal tissue. Full article
(This article belongs to the Special Issue Retinal Neurodegenerative Diseases: Molecular Targets Driving Neuroinflammation and Neuroprotection)
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20 pages, 7962 KiB  
Article
Retinal Ganglion Cell Loss and Microglial Activation in a SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis
by Pilar Rojas, Ana I. Ramírez, Manuel Cadena, José A. Fernández-Albarral, Elena Salobrar-García, Inés López-Cuenca, Irene Santos-García, Eva de Lago, José L. Urcelay-Segura, José M. Ramírez, Rosa de Hoz and Juan J. Salazar
Int. J. Mol. Sci. 2021, 22(4), 1663; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041663 - 07 Feb 2021
Cited by 6 | Viewed by 2790
Abstract
The neurodegenerative disease amyotrophic lateral sclerosis (ALS) affects the spinal cord, brain stem, and cerebral cortex. In this pathology, both neurons and glial cells are affected. However, few studies have analyzed retinal microglia in ALS models. In this study, we quantified the signs [...] Read more.
The neurodegenerative disease amyotrophic lateral sclerosis (ALS) affects the spinal cord, brain stem, and cerebral cortex. In this pathology, both neurons and glial cells are affected. However, few studies have analyzed retinal microglia in ALS models. In this study, we quantified the signs of microglial activation and the number of retinal ganglion cells (RGCs) in an SOD1G93A transgenic mouse model at 120 days (advanced stage of the disease) in retinal whole-mounts. For SOD1G93A animals (compared to the wild-type), we found, in microglial cells, (i) a significant increase in the area occupied by each microglial cell in the total area of the retina; (ii) a significant increase in the arbor area in the outer plexiform layer (OPL) inferior sector; (iii) the presence of cells with retracted processes; (iv) areas of cell groupings in some sectors; (v) no significant increase in the number of microglial cells; (vi) the expression of IFN-γ and IL-1β; and (vii) the non-expression of IL-10 and arginase-I. For the RGCs, we found a decrease in their number. In conclusion, in the SOD1G93A model (at 120 days), retinal microglial activation occurred, taking a pro-inflammatory phenotype M1, which affected the OPL and inner retinal layers and could be related to RGC loss. Full article
(This article belongs to the Special Issue Retinal Neurodegenerative Diseases: Molecular Targets Driving Neuroinflammation and Neuroprotection)
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19 pages, 5576 KiB  
Article
Heat Shock Protein 27 Injection Leads to Caspase Activation in the Visual Pathway and Retinal T-Cell Response
by Pia Grotegut, Philipp Johannes Hoerdemann, Sabrina Reinehr, Nupur Gupta, H. Burkhard Dick and Stephanie C. Joachim
Int. J. Mol. Sci. 2021, 22(2), 513; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020513 - 06 Jan 2021
Cited by 12 | Viewed by 2730
Abstract
Heat shock protein 27 (HSP27) is one of the small molecular chaperones and is involved in many cell mechanisms. Besides the known protective and helpful functions of intracellular HSP27, very little is known about the mode of action of extracellular HSP27. In a [...] Read more.
Heat shock protein 27 (HSP27) is one of the small molecular chaperones and is involved in many cell mechanisms. Besides the known protective and helpful functions of intracellular HSP27, very little is known about the mode of action of extracellular HSP27. In a previous study, we showed that intravitreal injection of HSP27 led to neuronal damage in the retina and optic nerve after 21 days. However, it was not clear which degenerative signaling pathways were induced by the injection. For this reason, the pathological mechanisms of intravitreal HSP27 injection after 14 days were investigated. Histological and RT-qPCR analyses revealed an increase in endogenous HSP27 in the retina and an activation of components of the intrinsic and extrinsic apoptosis pathway. In addition, an increase in nucleus factor-kappa-light-chain-enhancer of activated B cells (NFκB), as well as of microglia/macrophages and T-cells could be observed. In the optic nerve, however, only an increased apoptosis rate was detectable. Therefore, the activation of caspases and the induction of an incipient immune response seem to be the main triggers for retinal degeneration in this intravitreal HSP27 model. Full article
(This article belongs to the Special Issue Retinal Neurodegenerative Diseases: Molecular Targets Driving Neuroinflammation and Neuroprotection)
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Review

Jump to: Research

23 pages, 1866 KiB  
Review
Alzheimer’s Disease Seen through the Eye: Ocular Alterations and Neurodegeneration
by Daniel Romaus-Sanjurjo, Uxía Regueiro, Maite López-López, Laura Vázquez-Vázquez, Alberto Ouro, Isabel Lema and Tomás Sobrino
Int. J. Mol. Sci. 2022, 23(5), 2486; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052486 - 24 Feb 2022
Cited by 19 | Viewed by 5301
Abstract
Alzheimer’s Disease (AD) is one of the main neurodegenerative diseases worldwide. Unfortunately, AD shares many similarities with other dementias at early stages, which impedes an accurate premortem diagnosis. Therefore, it is urgent to find biomarkers to allow for early diagnosis of the disease. [...] Read more.
Alzheimer’s Disease (AD) is one of the main neurodegenerative diseases worldwide. Unfortunately, AD shares many similarities with other dementias at early stages, which impedes an accurate premortem diagnosis. Therefore, it is urgent to find biomarkers to allow for early diagnosis of the disease. There is increasing scientific evidence highlighting the similarities between the eye and other structures of the CNS, suggesting that knowledge acquired in eye research could be useful for research and diagnosis of AD. For example, the retina and optic nerve are considered part of the central nervous system, and their damage can result in retrograde and anterograde axon degeneration, as well as abnormal protein aggregation. In the anterior eye segment, the aqueous humor and tear film may be comparable to the cerebrospinal fluid. Both fluids are enriched with molecules that can be potential neurodegenerative biomarkers. Indeed, the pathophysiology of AD, characterized by cerebral deposits of amyloid-beta (Aβ) and tau protein, is also present in the eyes of AD patients, besides numerous structural and functional changes observed in the structure of the eyes. Therefore, all this evidence suggests that ocular changes have the potential to be used as either predictive values for AD assessment or as diagnostic tools. Full article
(This article belongs to the Special Issue Retinal Neurodegenerative Diseases: Molecular Targets Driving Neuroinflammation and Neuroprotection)
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20 pages, 2113 KiB  
Review
The Role of Inflammation in Retinal Neurodegeneration and Degenerative Diseases
by Geetika Kaur and Nikhlesh K. Singh
Int. J. Mol. Sci. 2022, 23(1), 386; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010386 - 30 Dec 2021
Cited by 31 | Viewed by 5008
Abstract
Retinal neurodegeneration is predominantly reported as the apoptosis or impaired function of the photoreceptors. Retinal degeneration is a major causative factor of irreversible vision loss leading to blindness. In recent years, retinal degenerative diseases have been investigated and many genes and genetic defects [...] Read more.
Retinal neurodegeneration is predominantly reported as the apoptosis or impaired function of the photoreceptors. Retinal degeneration is a major causative factor of irreversible vision loss leading to blindness. In recent years, retinal degenerative diseases have been investigated and many genes and genetic defects have been elucidated by many of the causative factors. An enormous amount of research has been performed to determine the pathogenesis of retinal degenerative conditions and to formulate the treatment modalities that are the critical requirements in this current scenario. Encouraging results have been obtained using gene therapy. We provide a narrative review of the various studies performed to date on the role of inflammation in human retinal degenerative diseases such as age-related macular degeneration, inherited retinal dystrophies, retinitis pigmentosa, Stargardt macular dystrophy, and Leber congenital amaurosis. In addition, we have highlighted the pivotal role of various inflammatory mechanisms in the progress of retinal degeneration. This review also offers an assessment of various therapeutic approaches, including gene-therapies and stem-cell-based therapies, for degenerative retinal diseases. Full article
(This article belongs to the Special Issue Retinal Neurodegenerative Diseases: Molecular Targets Driving Neuroinflammation and Neuroprotection)
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33 pages, 13975 KiB  
Review
Mitochondrial Retinopathies
by Massimo Zeviani and Valerio Carelli
Int. J. Mol. Sci. 2022, 23(1), 210; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010210 - 25 Dec 2021
Cited by 26 | Viewed by 5398
Abstract
The retina is an exquisite target for defects of oxidative phosphorylation (OXPHOS) associated with mitochondrial impairment. Retinal involvement occurs in two ways, retinal dystrophy (retinitis pigmentosa) and subacute or chronic optic atrophy, which are the most common clinical entities. Both can present as [...] Read more.
The retina is an exquisite target for defects of oxidative phosphorylation (OXPHOS) associated with mitochondrial impairment. Retinal involvement occurs in two ways, retinal dystrophy (retinitis pigmentosa) and subacute or chronic optic atrophy, which are the most common clinical entities. Both can present as isolated or virtually exclusive conditions, or as part of more complex, frequently multisystem syndromes. In most cases, mutations of mtDNA have been found in association with mitochondrial retinopathy. The main genetic abnormalities of mtDNA include mutations associated with neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) sometimes with earlier onset and increased severity (maternally inherited Leigh syndrome, MILS), single large-scale deletions determining Kearns–Sayre syndrome (KSS, of which retinal dystrophy is a cardinal symptom), and mutations, particularly in mtDNA-encoded ND genes, associated with Leber hereditary optic neuropathy (LHON). However, mutations in nuclear genes can also cause mitochondrial retinopathy, including autosomal recessive phenocopies of LHON, and slowly progressive optic atrophy caused by dominant or, more rarely, recessive, mutations in the fusion/mitochondrial shaping protein OPA1, encoded by a nuclear gene on chromosome 3q29. Full article
(This article belongs to the Special Issue Retinal Neurodegenerative Diseases: Molecular Targets Driving Neuroinflammation and Neuroprotection)
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16 pages, 1505 KiB  
Review
Molecular Mechanisms of Retinal Pigment Epithelium Dysfunction in Age-Related Macular Degeneration
by Jongmin Kim, Yeo Jin Lee and Jae Yon Won
Int. J. Mol. Sci. 2021, 22(22), 12298; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212298 - 14 Nov 2021
Cited by 24 | Viewed by 5250
Abstract
The retinal pigment epithelium (RPE), situated upon Bruch’s membrane, plays multiple roles in the ocular system by interacting with photoreceptors and. Therefore, dysfunction of the RPE causes diseases related to vision loss, such as age-related macular degeneration (AMD). Despite AMD being a global [...] Read more.
The retinal pigment epithelium (RPE), situated upon Bruch’s membrane, plays multiple roles in the ocular system by interacting with photoreceptors and. Therefore, dysfunction of the RPE causes diseases related to vision loss, such as age-related macular degeneration (AMD). Despite AMD being a global cause of blindness, the pathogenesis remains unclear. Understanding the pathogenesis of AMD is the first step for its prevention and treatment. This review summarizes the common pathways of RPE dysfunction and their effect in AMD. Potential treatment strategies for AMD based on targeting the RPE have also been discussed. Full article
(This article belongs to the Special Issue Retinal Neurodegenerative Diseases: Molecular Targets Driving Neuroinflammation and Neuroprotection)
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12 pages, 1039 KiB  
Review
The P2X7 Receptor: A Promising Pharmacological Target in Diabetic Retinopathy
by Matteo Tassetto, Anna Scialdone, Anna Solini and Francesco Di Virgilio
Int. J. Mol. Sci. 2021, 22(13), 7110; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22137110 - 01 Jul 2021
Cited by 16 | Viewed by 3218
Abstract
Diabetes is a worldwide emergency. Its chronic complications impose a heavy burden on patients, health systems, and on society as a whole. Diabetic retinopathy is one of the most common and serious complications of diabetes, and an established risk factor for blindness in [...] Read more.
Diabetes is a worldwide emergency. Its chronic complications impose a heavy burden on patients, health systems, and on society as a whole. Diabetic retinopathy is one of the most common and serious complications of diabetes, and an established risk factor for blindness in adults. Over 15 years of investigation led to the identification of vascular endothelial growth factor (VEGF) as a main pathogenic factor in diabetic retinopathy and to the introduction of highly effective anti-VEGF-based therapies, such as the monoclonal antibody bevacizumab or its fragment ranibizumab, which helped to prevent diabetes-related blindness in millions of patients. Recently, a pathogenic role for uncontrolled increases in the extracellular ATP concentration (eATP) and for overactivation of the purinergic receptor P2X7 (P2X7R) has been suggested. The P2X7R is an eATP-gated plasma membrane channel expressed in multiple tissues and organs, with a pleiotropic function in inflammation, immunity, cancer, and hormone and growth factor release. P2X7R stimulation or overexpression positively regulate the secretion and buildup of VEGF, thus promoting neo-angiogenesis in a wide variety of disease processes. In this review, we explore current evidence that supports the role of P2X7R receptor signaling in the pathogenesis of diabetic retinopathy, as well as the most appealing current therapeutical options for P2X7R targeting. Full article
(This article belongs to the Special Issue Retinal Neurodegenerative Diseases: Molecular Targets Driving Neuroinflammation and Neuroprotection)
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Review
Complement System and Potential Therapeutics in Age-Related Macular Degeneration
by Young Gun Park, Yong Soo Park and In-Beom Kim
Int. J. Mol. Sci. 2021, 22(13), 6851; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136851 - 25 Jun 2021
Cited by 19 | Viewed by 3745
Abstract
Age-related macular degeneration (AMD) is a complex multifactorial disease characterized in its late form by neovascularization (wet type) or geographic atrophy of the retinal pigment epithelium cell layer (dry type). The complement system is an intrinsic component of innate immunity. There has been [...] Read more.
Age-related macular degeneration (AMD) is a complex multifactorial disease characterized in its late form by neovascularization (wet type) or geographic atrophy of the retinal pigment epithelium cell layer (dry type). The complement system is an intrinsic component of innate immunity. There has been growing evidence that the complement system plays an integral role in maintaining immune surveillance and homeostasis in AMD. Based on the association between the genotypes of complement variants and AMD occurrence and the presence of complement in drusen from AMD patients, the complement system has become a therapeutic target for AMD. However, the mechanism of complement disease propagation in AMD has not been fully understood. This concise review focuses on an overall understanding of the role of the complement system in AMD and its ongoing clinical trials. It provides further insights into a strategy for the treatment of AMD targeting the complement system. Full article
(This article belongs to the Special Issue Retinal Neurodegenerative Diseases: Molecular Targets Driving Neuroinflammation and Neuroprotection)
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