The murine models of Alzheimer's disease (AD) have advanced our understanding of the pathophysiology. In vivo studies of the retina using optical coherence tomography (OCT) have complemented ...histological methods; however, the lack of standardisation in OCT methodologies for murine models of AD has led to significant variations in the results of different studies. A literature search in PubMed and Scopus has been performed to review the different methods used in these models using OCT and to analyse the methodological characteristics of each study. In addition, some recommendations are offered to overcome the challenges of using OCT in murine models. The results reveal a lack of consensus on OCT device use, retinal area analysed, segmentation techniques, and analysis software. Although some studies use the same OCT device, variations in other parameters make the direct comparison of results difficult. Standardisation of retinal analysis criteria in murine models of AD using OCT is crucial to ensure consistent and comparable results. This implies the application of uniform measurement and segmentation protocols. Despite the absence of standardisation, OCT has proven valuable in advancing our understanding of the pathophysiology of AD.
Ocular neurodegenerative diseases such as glaucoma, diabetic retinopathy, and age-related macular degeneration are common retinal diseases responsible for most of the blindness causes in the ...working-age and elderly populations in developed countries. Many of the current treatments used in these pathologies fail to stop or slow the progression of the disease. Therefore, other types of treatments with neuroprotective characteristics may be necessary to allow a more satisfactory management of the disease. Citicoline and coenzyme Q10 are molecules that have neuroprotective, antioxidant, and anti-inflammatory properties, and their use could have a beneficial effect in ocular neurodegenerative pathologies. This review provides a compilation, mainly from the last 10 years, of the main studies that have been published on the use of these drugs in these neurodegenerative diseases of the retina, analyzing the usefulness of these drugs in these pathologies.
Glaucoma is a neurodegenerative disease that causes blindness. In this study, we aimed to evaluate the protective role of cilastatin (CIL), generally used in the treatment of nephropathologies ...associated with inflammation, in an experimental mouse model based on unilateral (left) laser-induced ocular hypertension (OHT). Male Swiss mice were administered CIL daily (300 mg/kg, i.p.) two days before OHT surgery until sacrifice 3 or 7 days later. Intraocular Pressure (IOP), as well as retinal ganglion cell (RGC) survival, was registered, and the inflammatory responses of macroglial and microglial cells were studied via immunohistochemical techniques. Results from OHT eyes were compared to normotensive contralateral (CONTRA) and naïve control eyes considering nine retinal areas and all retinal layers. OHT successfully increased IOP values in OHT eyes but not in CONTRA eyes; CIL did not affect IOP values. Surgery induced a higher loss of RGCs in OHT eyes than in CONTRA eyes, while CIL attenuated this loss. Similarly, surgery increased macroglial and microglial activation in OHT eyes and to a lesser extent in CONTRA eyes; CIL prevented both macroglial and microglial activation in OHT and CONTRA eyes. Therefore, CIL arises as a potential effective strategy to reduce OHT-associated damage in the retina of experimental mice.
Dravet syndrome (DS) is an epileptic encephalopathy caused by mutations in the
gene encoding the α1 subunit of the Nav1.1 sodium channel, which is associated with recurrent and generalized seizures, ...even leading to death. In experimental models of DS, histological alterations have been found in the brain; however, the retina is a projection of the brain and there are no studies that analyze the possible histological changes that may occur in the disease. This study analyzes the retinal histological changes in glial cells (microglia and astrocytes), retinal ganglion cells (RGCs) and GABAergic amacrine cells in an experimental model of DS (Syn-Cre/Scn1a
) compared to a control group at postnatal day (PND) 25. Retinal whole-mounts were labeled with anti-GFAP, anti-Iba-1, anti-Brn3a and anti-GAD65/67. Signs of microglial and astroglial activation, and the number of Brn3a+ and GAD65+67+ cells were quantified. We found retinal activation of astroglial and microglial cells but not death of RGCs and GABAergic amacrine cells. These changes are similar to those found at the level of the hippocampus in the same experimental model in PND25, indicating a relationship between brain and retinal changes in DS. This suggests that the retina could serve as a possible biomarker in DS.
Glaucoma is a neurodegenerative disease of the retina characterized by the irreversible loss of retinal ganglion cells (RGCs) leading to visual loss. Degeneration of RGCs and loss of their axons, as ...well as damage and remodeling of the lamina cribrosa are the main events in the pathogenesis of glaucoma. Different molecular pathways are involved in RGC death, which are triggered and exacerbated as a consequence of a number of risk factors such as elevated intraocular pressure (IOP), age, ocular biomechanics, or low ocular perfusion pressure. Increased IOP is one of the most important risk factors associated with this pathology and the only one for which treatment is currently available, nevertheless, on many cases the progression of the disease continues, despite IOP control. Thus, the IOP elevation is not the only trigger of glaucomatous damage, showing the evidence that other factors can induce RGCs death in this pathology, would be involved in the advance of glaucomatous neurodegeneration. The underlying mechanisms driving the neurodegenerative process in glaucoma include ischemia/hypoxia, mitochondrial dysfunction, oxidative stress and neuroinflammation. In glaucoma, like as other neurodegenerative disorders, the immune system is involved and immunoregulation is conducted mainly by glial cells, microglia, astrocytes, and Müller cells. The increase in IOP produces the activation of glial cells in the retinal tissue. Chronic activation of glial cells in glaucoma may provoke a proinflammatory state at the retinal level inducing blood retinal barrier disruption and RGCs death. The modulation of the immune response in glaucoma as well as the activation of glial cells constitute an interesting new approach in the treatment of glaucoma.
Alzheimer's disease (AD) is the most common form of dementia affecting the central nervous system, and alteration of several visual structures has been reported. Structural retinal changes are ...usually accompanied by changes in visual function in this disease. The aim of this study was to analyse the differences in visual function at different stages of the pathology (family history group (FH+), mild cognitive impairment (MCI), mild AD and moderate AD) in comparison with a control group of subjects with no cognitive decline and no family history of AD.
We included 53 controls, 13 subjects with FH+, 23 patients with MCI, 25 patients with mild AD and, 21 patients with moderate AD. All were ophthalmologically healthy. Visual acuity (VA), contrast sensitivity (CS), colour perception, visual integration, and fundus examination were performed.
The analysis showed a statistically significant decrease in VA, CS and visual integration score between the MCI, mild AD and moderate AD groups compared to the control group. In the CS higher frequencies and in the colour perception test (total errors number), statistically significant differences were also observed in the MCI, mild AD and moderate AD groups with respect to the FH+ group and also between the control and AD groups. The FH+ group showed no statistically significant difference in visual functions compared to the control group. All the test correlated with the Mini Mental State Examination score and showed good predictive value when memory decline was present, with better values when AD was at a more advanced stage.
Alterations in visual function appear in subjects with MCI and evolve when AD is established, being stable in the initial stages of the disease (mild AD and moderate AD). Therefore, visual psychophysical tests are a useful, simple and complementary tool to neuropsychological tests to facilitate diagnosis in the preclinical and early stages of AD.
Glaucoma is a neurodegenerative disease that leads to the loss of retinal ganglion cells (RGC) and thus to blindness. There are numerous experimental models used for the study of this pathology. ...Among the different models, episcleral vein photocoagulation is one of the most widely used. In this model there is a transient increase in intraocular pressure that returns to normal values about 7 days after induction of ocular hypertension (OHT). In addition, typical glaucoma changes, such as loss of RGC, thinning of the optic nerve fiber layer, and glial activation, occur in this model. All these changes have been described in detail over time after OHT induction. In this chapter, we describe the detailed method of OHT induction in Swiss albino mice by diode laser photocoagulation of limbal and episcleral veins.
Purpose: The aim of this study was to analyse the effects of unilateral laser‐induced ocular hypertension (OHT) on macroglia in OHT and contralateral eyes at different time points after laser ...treatment (1, 3, 5, 8 and 15 days).
Methods: Two groups of albino Swiss mice: naïve group (n = 6) and OHT group (n = 30, six animals for each time study group). In the OHT group, OHT was induced by laser photocoagulation of the limbal and episcleral veins of the left eyes. Retinal whole‐mounts were used to visualize the astroglial plexus throughout the retinal extension, analysing the GFAP‐labelled retinal area (GFAP‐RA), the intensity of GFAP labeling (GFAP‐IRI), and the intensity of MHC‐II expression (MHC‐II‐IRI) in both OHT eyes and normotensive contralateral eyes compared to naïve eyes.
Results: In OHT and contralateral eyes, with respect to naïve eyes, at all the time points, we found the following: (i) astrocytes with thicker somas and more secondary processes, mainly in the intermediate (IR) and peripheral retina (PR); (ii) astrocytes with low GFAP‐IRI and only primary processes near the optic disc (OD); (iii) increased total GFAP‐RA, which was higher at 3 and 5 days, except for at 15 days; (iv) increased GFAP‐IRI in the IR and especially in the PR: (v) decreased GFAP‐IRI near the OD, mainly at 1 and 5 days; (vi) a significant increase in MHC‐II‐IRI, which was higher in the IR and PR; and (vii) GFAP+ and MHC‐II+ immunolabelling in the Müller glia.
Conclusions: Increased IOP leads, both in OHT eyes and in their normotensive contralateral eye, to macroglial activation, demonstrated both by morphologic changes and by the overexpression of GFAP and MHC‐II. The main signs of activation were observed mainly in the IR and PR, being more intense at 3 and 5 days after induction. However, in the OD, astrocytes showed low expression of GFAP and MHC‐II. The bilateral macroglial activation observed in this study would be triggered by the immune response associated with neuroinflammation.
Purpose: The aim of this work is analyse and characterize retinal drusen in cognitively healthy subjects at high risk of developing Alzheimer's disease (AD) (having a family history (FH+) of AD and ...carrying ɛ4 allele for the ApoE gene) compared to control subjects.
Methods: Subjects are classified by their AD HF (HF‐ or HF+) and their ApoE ɛ4 allelic characterization (ApoE ɛ4‐ or ApoE ɛ4+) to analyse retinal drusen by OCT. Hypercholesterolemia (HCL), blood high pressure (HBP) and diabetes mellitus are also considered in this analysis. In addition, we analysed choroidal thickness by OCT.
Results: When we compared the drusen number between groups taking account the HCL, there was statistical significance between the FH‐ ApoE ɛ4‐ HCL+ group and (i) FH+ ApoE ɛ4‐ HCL+ and (ii) FH+ ApoE ɛ4+ HCL‐ groups. Considering HBP and comparing the drusen number between the study groups, we found statistically significant differences when comparing the FH‐ ApoE ɛ4‐ HBP‐ group and the FH+ ApoE ɛ4+ HBP+ group. We also found statistically significant differences in the number of drusen when comparing the FH‐ ApoE ɛ4‐ HBP+ group with: (i) FH+ ApoE ɛ4‐ HBP‐ group; and (ii) FH+ ApoE ɛ4+ HBP+ group).
Conclusions: In conclusion, there does not appear to be a relationship between AD HF or any of the ApoE isoforms and the presence or absence of drusen. Subjects with drusen show choroidal thinning compared with patients without drusen, reaching statistical significance in the group of participants with an AD HF, without ApoE ɛ4, and with HCL. This thinning could trigger changes in choroidal perfusion that could give rise to the deposits that generate drusen.
Macroglia (astrocytes and Müller glia) may play an important role in the pathogenesis of glaucoma. In a glaucoma mouse model, we studied the effects of unilateral laser-induced ocular hypertension ...(OHT) on macroglia in OHT and contralateral eyes at different time points after laser treatment (1, 3, 5, 8 and 15 days) using anti-GFAP and anti-MHC-II, analyzing the morphological changes, GFAP-labelled retinal area (GFAP-PA), and GFAP and MHC-II immunoreactivity intensities ((GFAP-IRI and MHC-II-IRI)). In OHT and contralateral eyes, with respect to naïve eyes, at all the time points, we found the following: (i) astrocytes with thicker somas and more secondary processes, mainly in the intermediate (IR) and peripheral retina (PR); (ii) astrocytes with low GFAP-IRI and only primary processes near the optic disc (OD); (iii) an increase in total GFAP-RA, which was higher at 3 and 5 days, except for at 15 days; (iv) an increase in GFAP-IRI in the IR and especially in the PR; (v) a decrease in GFAP-IRI near the OD, especially at 1 and 5 days; (vi) a significant increase in MHC-II-IRI, which was higher in the IR and PR; and (vii) the Müller glia were GFAP+ and MHC-II+. In conclusion, in this model of glaucoma, there is a bilateral macroglial activation maintained over time involved in the inflammatory glaucoma process.
