Activation of retinoid X receptors protects retinal neurons and pigment epithelial cells from BMAA-induced death.

Exposure to the non-protein amino acid cyanotoxin β-N-methylamino-L-alanine (BMAA), released by cyanobacteria found in many water reservoirs has been associated with neurodegenerative diseases. We previously demonstrated that BMAA induced cell death in both retina photoreceptors (PHRs) and amacrine neurons by triggering different molecular pathways, as activation of NMDA receptors and formation of carbamate-adducts was only observed in amacrine cell death. We established that activation of Retinoid X Receptors (RXR) protects retinal cells, including retina pigment epithelial (RPE) cells from oxidative stress-induced apoptosis.

Sphingosine-1-phosphate and ceramide-1-phosphate promote migration, pro-inflammatory and pro-fibrotic responses in retinal pigment epithelium cells.

Retinal pigment epithelium (RPE) cells, essential for preserving retina homeostasis, also contribute to the development of retina proliferative diseases, through their exacerbated migration, epithelial to mesenchymal transition (EMT) and inflammatory response. Uncovering the mechanisms inducing these changes is crucial for designing effective treatments for these pathologies. Sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) are bioactive sphingolipids that promote migration and inflammation in several cell types; we recently established that they stimulate the migration of retina Müller glial cells (Simón et al.

Retina stem cells, hopes and obstacles.

Retinal degeneration is a major contributor to visual dysfunction worldwide. Although it comprises several eye diseases, loss of retinal pigment epithelial (RPE) and photoreceptor cells are the major contributors to their pathogenesis. Early therapies included diverse treatments, such as provision of anti-vascular endothelial growth factor and many survival and trophic factors that, in some cases, slow down the progression of the degeneration, but do not effectively prevent it.

Retinoid X receptor activation promotes photoreceptor survival and modulates the inflammatory response in a mouse model of retinitis pigmentosa.

Photoreceptor cell (PHR) death is a hallmark of most retinal neurodegenerative diseases, in which inflammation plays a critical role. Activation of retinoid X receptors (RXR) modulates and integrates multiple cell functions, and has beneficial effects in animal models of chronic inflammatory diseases. Nonetheless, the mechanisms involved and their role in retina neuroprotection are poorly understood.

Pigment epithelium-derived factor (PEDF) and derived peptides promote survival and differentiation of photoreceptors and induce neurite-outgrowth in amacrine neurons.

Pigment epithelium-derived factor (PEDF) is a cytoprotective protein for the retina. We hypothesize that this protein acts on neuronal survival and differentiation of photoreceptor cells in culture. The purpose of the present study was to evaluate the neurotrophic effects of PEDF and its fragments in an in vitro model of cultured primary retinal neurons that die spontaneously in the absence of trophic factors.

Ceramide-1-phosphate promotes the migration of retina Müller glial cells.

Müller glial cells, the major glial cell type in the retina, are activated by most retina injuries, leading to an increased proliferation and migration that contributes to visual dysfunction. The molecular cues involved in these processes are still ill defined. We demonstrated that sphingosine-1-phosphate (S1P), a bioactive sphingolipid, promotes glial migration.

Damaging effects of BMAA on retina neurons and Müller glial cells.

B-N-methylamino-L-alanine (BMAA), a cyanotoxin produced by most cyanobacteria, has been proposed to cause long term damages leading to neurodegenerative diseases, including Amyotrophic Lateral Sclerosis/Parkinsonism Dementia complex (ALS/PDC) and retinal pathologies. Previous work has shown diverse mechanisms leading to BMAA-induced degeneration; however, the underlying mechanisms of toxicity affecting retina cells are not fully elucidated. We here show that BMAA treatment of rat retina neurons in vitro induced nuclear fragmentation and cell death in both photoreceptors (PHRs) and amacrine neurons, provoking mitochondrial membrane depolarization.

Sphingolipids as critical players in retinal physiology and pathology.

Sphingolipids have emerged as bioactive lipids involved in the regulation of many physiological and pathological processes. In the retina, they have been established to participate in numerous processes, such as neuronal survival and death, proliferation and migration of neuronal and vascular cells, inflammation, and neovascularization. Dysregulation of sphingolipids is therefore crucial in the onset and progression of retinal diseases.

A Defective Crosstalk Between Neurons and Müller Glial Cells in the Retina Impairs the Regenerative Potential of Glial Stem Cells.

Müller glial cells (MGC) are stem cells in the retina. Although their regenerative capacity is very low in mammals, the use of MGC as stem cells to regenerate photoreceptors (PHRs) during retina degenerations, such as in retinitis pigmentosa, is being intensely studied. Changes affecting PHRs in diseased retinas have been thoroughly investigated; however, whether MGC are also affected is still unclear.

Sphingolipids as Emerging Mediators in Retina Degeneration.

The sphingolipids ceramide (Cer), sphingosine-1-phosphate (S1P), sphingosine (Sph), and ceramide-1-phosphate (C1P) are key signaling molecules that regulate major cellular functions. Their roles in the retina have gained increasing attention during the last decade since they emerge as mediators of proliferation, survival, migration, neovascularization, inflammation and death in retina cells. As exacerbation of these processes is central to retina degenerative diseases, they appear as crucial players in their progression.

Ceramide Induces the Death of Retina Photoreceptors Through Activation of Parthanatos.

Ceramide (Cer) has a key role inducing cell death and has been proposed as a messenger in photoreceptor cell death in the retina. Here, we explored the pathways induced by C-acetylsphingosine (C-Cer), a cell-permeable Cer, to elicit photoreceptor death. Treating pure retina neuronal cultures with 10 μM C-Cer for 6 h selectively induced photoreceptor death, decreasing mitochondrial membrane potential and increasing the formation of reactive oxygen species (ROS).

Microsaccadic behavior when developing a complex dynamical activity.

Microsaccade are sensitive to changes of perceptual inputs as well as modulations of cognitive states. There are just a few works analyzing microsaccade while subjects are processing complex information and fewer when doing predictions about upcoming events. To evaluate whether contextual predictability would change microsaccadic behavior, we evaluated microsaccade of twenty one persons when reading 40 regular sentences and 40 proverbs.

Protective effects of retinoid x receptors on retina pigment epithelium cells.

Age-related macular degeneration (AMD) is among the main pathologies leading to blindness in adults and has currently no cure or effective treatment. Selective apoptosis of retina pigment epithelial (RPE) cells results in the progressive loss of photoreceptor neurons, with the consequent gradual vision loss. Oxidative stress plays an important role in this process.

Patients with Mild Alzheimer's Disease Fail When Using Their Working Memory: Evidence from the Eye Tracking Technique.

Patients with Alzheimer's disease (AD) develop progressive language, visuoperceptual, attentional, and oculomotor changes that can have an impact on their reading comprehension. However, few studies have examined reading behavior in AD, and none have examined the contribution of predictive cueing in reading performance. For this purpose we analyzed the eye movement behavior of 35 healthy readers (Controls) and 35 patients with probable AD during reading of regular and high-predictable sentences.

Synthesis of docosahexaenoic acid from eicosapentaenoic acid in retina neurons protects photoreceptors from oxidative stress.

Oxidative stress is involved in activating photoreceptor death in several retinal degenerations. Docosahexaenoic acid (DHA), the major polyunsaturated fatty acid in the retina, protects cultured retina photoreceptors from apoptosis induced by oxidative stress and promotes photoreceptor differentiation. Here, we investigated whether eicosapentaenoic acid (EPA), a metabolic precursor to DHA, had similar effects and whether retinal neurons could metabolize EPA to DHA.

Sphingosine-1-Phosphate Is a Crucial Signal for Migration of Retina Müller Glial Cells.

Purpose: Migration of Müller glial cells is enhanced in proliferative retinopathies, but the mechanisms involved are ill defined. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid synthesized by sphingosine kinase (SphK), which promotes proliferation, migration, and inflammation, acting as an intracellular mediator and activating a family of membrane receptors (S1PRs). We investigated whether S1P regulated glial migration.

Light, lipids and photoreceptor survival: live or let die?

Due to its constant exposure to light and its high oxygen consumption the retina is highly sensitive to oxidative damage, which is a common factor in inducing the death of photoreceptors after light damage or in inherited retinal degenerations. The high content of docosahexaenoic acid (DHA), the major polyunsaturated fatty acid in the retina, has been suggested to contribute to this sensitivity. DHA is crucial for developing and preserving normal visual function.

Lack of contextual-word predictability during reading in patients with mild Alzheimer disease.

In the present work we analyzed the effect of contextual word predictability on the eye movement behavior of patients with mild Alzheimer disease (AD) compared to age-matched controls, by using the eyetracking technique and lineal mixed models. Twenty AD patients and 40 age-matched controls participated in the study. We first evaluated gaze duration during reading low and highly predictable sentences.

Eye movement alterations during reading in patients with early Alzheimer disease.

Purpose: Eye movements follow a reproducible pattern during normal reading. Each eye movement ends up in a fixation point, which allows the brain to process the incoming information and to program the following saccade. Alzheimer disease (AD) produces eye movement abnormalities and disturbances in reading.

Retinoid X receptor activation is essential for docosahexaenoic acid protection of retina photoreceptors.

We have established that docosahexaenoic acid (DHA), the major polyunsaturated fatty acid in the retina, promotes survival of rat retina photoreceptors during early development in vitro and upon oxidative stress by activating the ERK/MAPK signaling pathway. Here we have investigated whether DHA turns on this pathway through activation of retinoid X receptors (RXRs) or by inducing tyrosine kinase (Trk) receptor activation. We also evaluated whether DHA release from phospholipids was required for its protective effect.

Retinoic acid promotes apoptosis and differentiation in photoreceptors by activating the P38 MAP kinase pathway.

Purpose: Retinoic acid (RA) has a critical role during development of the retina. We investigated RA effects on photoreceptor apoptosis and differentiation, and the intracellular pathways involved.

Methods: Rat retinal neuronal cultures were supplemented with RA with or without docosahexaenoic acid (DHA), a photoreceptor survival factor, and photoreceptor apoptosis and differentiation were evaluated at different times of development.

Leukemia inhibitory factor coordinates the down-regulation of the visual cycle in the retina and retinal-pigmented epithelium.

Leukemia inhibitory factor (LIF), an interleukin-6 family neurocytokine, is up-regulated in response to different types of retinal stress and has neuroprotective activity through activation of the gp130 receptor/STAT3 pathway. We observed that LIF induces rapid, robust, and sustained activation of STAT3 in both the retina and retinal pigmented epithelium (RPE). Here, we tested whether LIF-induced STAT3 activation within the RPE can down-regulate RPE65, the central enzyme in the visual cycle that provides the 11-cis-retinal chromophore to photoreceptors in vivo.

Müller glial cells induce stem cell properties in retinal progenitors in vitro and promote their further differentiation into photoreceptors.

Using stem cells to replace lost neurons is a promising strategy for treating retinal neurodegenerative diseases. Among their multiple functions, Müller glial cells are retina stem cells, with a robust regenerative potential in lower vertebrates, which is much more restricted in mammals. In rodents, most retina progenitors exit the cell cycle immediately after birth, differentiate as neurons, and then cannot reenter the cell cycle.

Ceramide-1-phosphate, a new mediator of development and survival in retina photoreceptors.

PURPOSE. Simple sphingolipids control crucial cellular processes in several cell types. Previous work demonstrated that sphingolipids, such as ceramide, sphingosine, and sphingosine-1-phosphate, are key mediators in the regulation of survival, differentiation, and proliferation of retina photoreceptors.

Regulating survival and development in the retina: key roles for simple sphingolipids.

Many sphingolipids have key functions in the regulation of crucial cellular processes. Ceramide (Cer) and sphingosine (Sph) induce growth arrest and cell death in multiple situations of cellular stress. On the contrary, sphingosine-1-phosphate (S1P), the product of Sph phosphorylation, promotes proliferation, differentiation, and survival in different cell systems.