Abstract: Subretinal inflammation plays a critical role in retinal degenerative diseases. Although activated macrophages have been shown to play a key role in the progression of retinopathies and specifically in age-related macular degeneration, little is known about the mechanisms involved in the loss of photoreceptors leading to vision impairment. In our study on retinal damages induced by photo-oxidative stress, we have observed that CD36-deficient mice featured less subretinal macrophage accumulation with attenuated photoreceptor degeneration compared to wild-type (WT) mice. Treatment with CD36-selective azapeptide ligand (labelled MPE-001) as modulator of the inflammatory environment of the retina reduced subretinal macrophage/activated microglia accumulation with preservation of photoreceptor layers and function assessed by ERG in WT, in a CD36-dependent manner. The azapeptide modulated the transcriptome of subretinal macrophage/activated microglia by reducing pro-inflammatory markers. In isolated macrophages, the CD36-selective azapeptide induced dissociation of the CD36-TLR2/6 heterodimer complex (using FRET) altering the TLR2 signaling pathway, thus decreasing NF-KB activation and inflammasome activity. The azapeptide also incurred cytoprotection against photoreceptor apoptosis elicited by activated macrophages. These findings suggest that the azapeptide as ligand of co-receptor CD36 decreases the inflammatory response by modulating CD36-TLR2/6 complex signaling pathway in macrophages, and suggests its potential application in the treatment of retinal degenerative diseases.
Abstract: Genetic studies have revealed that variants in genes that encode regulators of the complement system are major risk factors for the development of age-related macular degeneration (AMD). The biochemical consequences of the common polymorphism in complement factor H (Tyr402His) include increased formation of the membrane attack complex (MAC), which is deposited at the level of the inner choroid and choriocapillaris. Whereas the MAC is normally protective against foreign pathogens, it can also damage resident bystander cells when it is insufficiently regulated. Indeed, human maculas with early AMD show loss of endothelial cells in the choriocapillaris, the principal site of MAC activation. Modeling of MAC injury of choroidal endothelial cells in vitro reveals that these cells are susceptible to cell lysis by the MAC, and that unlysed cells alter their gene expression profile to undergo a pro-angiogenic phenotype that includes increased expression of matrix metalloproteinase-9. Strategies for protecting choriocapillaris endothelial cells from MAC-mediated lysis and for replacing lysed endothelial cells will be discussed.
Abstract: The bone morphogenetic protein (BMP) family of proteins has a multitude of roles throughout the body. It plays important roles in development and in the adult vascular endothelium, by modulating the angiogenic response. The endothelial-specific receptor BMP receptor Alk1 is of particular importance in the proper remodeling of the vasculature and its ligand BMP9 has been shown to be a potent inhibitor of neovascularization. Dysregulated BMP signaling has been linked to multiple vascular diseases and can lead to the abnormal angiogenesis. We therefore investigated the role of BMP9/Alk1 signaling in retinal angiogenesis, and its therapeutic implications for vascular pathologies of the eye.
Abstract: Autophagy recycles intracellular substrate in part to fuel mitochondria during starvation. Deregulated autophagy caused by dyslipidemia, oxidative stress, and aging is associated with early signs of age-related macular degeneration (AMD), such as lipofuscin and perhaps drusen accumulation. Intracellular nutrient sensors for glucose and amino acids regulate autophagy. The role of lipid sensors in controlling autophagy, however, remains ill-defined. Here we will show that abundant circulating lipids trigger a satiety signal through FA receptors that restrain autophagy and oxidative mitochondrial metabolism. In the presence of excess dietary lipids, fatty acid sensors might protect tissues with high metabolic rates against lipotoxicity, favoring their storage, instead, in adipose tissues. However, sustained exposure to lipid reduces retinal metabolic efficiency. In photoreceptors with high metabolic needs, it predisposes to an energy failure and triggers compensatory albeit pathological angiogenesis, leading to blinding neovascular AMD.
Abstract: Ocular vessel networks develop in a highly stereotyped fashion. Abnormal ocular angiogenesis is associated with major diseases including age-related macular degeneration and diabetic retinopathy. Better understanding of mechanisms driving angiogenesis is expected to uncover novel targets to prevent vision loss. Capillary growth is driven by endothelial tip cells, which are selected by dynamic interplay between VEGF, Notch and BMP signaling, with VEGF acting as a positive regulator, and Notch and the BMP receptor Alk1 acting as negative regulators of tip cell formation. The concerted interplay between these molecules ensures that appropriate tip cell numbers leading new vessel branches are formed. In addition, guidance receptors including Neuropilins and Roundabout receptors contribute to vascular patterning by regulating VEGF and BMP signaling. Possibilities to target these pathways during pathological ocular neovascularization will be discussed.
Abstract: Disorders of lipid metabolism and macrophage function have been implicated in tissue aging and in diseases such as age-related macular degeneration (AMD). Genetic studies and expression profiling have identified widespread abnormalities in cholesterol metabolism in the aging macrophage. In addition, the molecular pathways that regulate the transition from aging to disease have not been elucidated. The current status regarding the mechanisms that regulate macrophage aging and the molecular mechanisms of transition to disease in the context of AMD will be presented with a special focus on factors that influence pathologic angiogenesis and neurodegeneration.
Abstract: The inverted retina is a basic characteristic of the vertebrate eye. This implies that vertebrates must have a common ancestor with an inverted retina. Of the two groups of chordates, cephalochordates have an inverted retina and urochordates a direct retina. Surprisingly, recent genetics studies favor urochordates as the closest ancestor to vertebrates. The evolution of increasingly complex organs such as the eye implies not only tissular but also structural modifications at the organ level. How these configurational modifications give rise to a functional eye at any step is still subject to debate and speculation. Here we propose an orderly sequence of phylogenetic events that closely follows the sequence of developmental eye formation in extant vertebrates. The progressive structural complexity has been clearly recorded during vertebrate development at the period of organogenesis. Matching the chain of increasing eye complexity in Mollusca that leads to the bicameral eye of the octopus and the developmental sequence in vertebrates, we delineate the parallel evolution of the two-chambered eye of vertebrates starting with an early ectodermal eye. This sequence allows for some interesting predictions regarding the eyes of not preserved intermediary species. The clue to understanding the inverted retina of vertebrates and the similarity between the sequence followed by Mollusca and chordates is the notion that the eye in both cases is an ectodermal structure, in contrast to an exclusively (de novo) neuroectodermal origin in the eye of vertebrates. This analysis places cephalochordates as the closest branch to vertebrates contrary to urochordates, claimed as a closer branch by some researchers that base their proposals in a genetic analysis.
Abstract: Pediatric neuro-ophthalmology is a subspecialty within neuro-ophthalmology. Pediatric neuro-ophthalmic diseases must be considered separate from their adult counterparts, due to the distinctive nature of the examination, clinical presentations, and management choices. This manuscript will highlight four common pediatric neuro-ophthalmic disorders by describing common clinical presentations, recommended management, and highlighting recent developments. Diseases discussed include pediatric idiopathic intracranial hypertension (IIH), pseudopapilledema, optic neuritis (ON) and optic pathway gliomas (OPG). The demographics, diagnosis and management of common pediatric neuro-ophthalmic disease require a working knowledge of the current research presented herein. Special attention should be placed on the differences between pediatric and adult entities such that children can be appropriately diagnosed and treated.
