PPARβ/δ selectively regulates phenotypic features of age-related macular degeneration.

Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) is a nuclear receptor that regulates differentiation, inflammation, lipid metabolism, extracellular matrix remodeling, and angiogenesis in multiple tissues. These pathways are also central to the pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss globally. With the goal of identifying signaling pathways that may be important in the development of AMD, we investigated the impact of PPARβ/δ activation on ocular tissues affected in the disease. PPARβ/δ is expressed and can be activated in AMD vulnerable cells, including retinal pigment epithelial (RPE) and choroidal endothelial cells. Further, PPARβ/δ knockdown modulates AMD-related pathways selectively. Specifically, genetic ablation of Pparβ/δ in aged mice resulted in exacerbation of several phenotypic features of early dry AMD, but attenuation of experimentally induced choroidal neovascular (CNV) lesions. Antagonizing PPARβ/δ in both in vitro angiogenesis assays and in the in vivo experimentally induced CNV model, inhibited angiogenesis and angiogenic pathways, while ligand activation of PPARβ/δ, in vitro, decreased RPE lipid accumulation, characteristic of dry AMD. This study demonstrates for the first time, selective regulation of a nuclear receptor in the eye and establishes that selective targeting of PPARβ/δ may be a suitable strategy for treatment of different clinical sub-types of AMD

Impaired monocyte cholesterol clearance initiates age-related retinal degeneration and vision loss

Advanced age-related macular degeneration (AMD), the leading cause of blindness among people over 50 years of age, is characterized by atrophic neurodegeneration or pathologic angiogenesis. Early AMD is characterized by extracellular cholesterol-rich deposits underneath the retinal pigment epithelium (RPE) called drusen or in the subretinal space called subretinal drusenoid deposits (SDD) that drive disease progression. However, mechanisms of drusen and SDD biogenesis remain poorly understood. Although human AMD is characterized by abnormalities in cholesterol homeostasis and shares phenotypic features with atherosclerosis, it is unclear whether systemic immunity or local tissue metabolism regulates this homeostasis. Here, we demonstrate that targeted deletion of macrophage cholesterol ABC transporters A1 (ABCA1) and -G1 (ABCG1) leads to age-associated extracellular cholesterol-rich deposits underneath the neurosensory retina similar to SDD seen in early human AMD. These mice also develop impaired dark adaptation, a cardinal feature of RPE cell dysfunction seen in human AMD patients even before central vision is affected. Subretinal deposits in these mice progressively worsen with age, with concomitant accumulation of cholesterol metabolites including several oxysterols and cholesterol esters causing lipotoxicity that manifests as photoreceptor dysfunction and neurodegeneration. These findings suggest that impaired macrophage cholesterol transport initiates several key elements of early human AMD, demonstrating the importance of systemic immunity and aging in promoting disease manifestation. Polymorphisms in genes involved with cholesterol transport and homeostasis are associated with a significantly higher risk of developing AMD, thus making these studies translationally relevant by identifying potential targets for therapy

The Mechanism of Diabetic Retinopathy Pathogenesis Unifying Key Lipid Regulators, Sirtuin 1 and Liver X Receptor

Diabetic retinopathy (DR) is a complication secondary to diabetes and is the number one cause of blindness among working age individuals worldwide. Despite recent therapeutic breakthroughs using pharmacotherapy, a cure for DR has yet to be realized. Several clinical trials have highlighted the vital role dyslipidemia plays in the progression of DR. Additionally, it has recently been shown that activation of Liver X receptor (LXRα/LXRβ) prevents DR in diabetic animal models. LXRs are nuclear receptors that play key roles in regulating cholesterol metabolism, fatty acid metabolism and inflammation. In this manuscript, we show insight into DR pathogenesis by demonstrating an innovative signaling axis that unifies key metabolic regulators, Sirtuin 1 and LXR, in modulating retinal cholesterol metabolism and inflammation in the diabetic retina. Expression of both regulators, Sirtuin 1 and LXR, are significantly decreased in diabetic human retinal samples and in a type 2 diabetic animal model. Additionally, activation of LXR restores reverse cholesterol transport, prevents inflammation, reduces pro-inflammatory macrophages activity and prevents the formation of diabetes-induced acellular capillaries. Taken together, the work presented in this manuscript highlights the important role lipid dysregulation plays in DR progression and offers a novel potential therapeutic target for the treatment of DR

LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target

Effective treatments and animal models for the most prevalent neurodegenerative form of blindness in elderly people, called age-related macular degeneration (AMD), are lacking. Genome-wide association studies have identified lipid metabolism and inflammation as AMD-associated pathogenic pathways. Given liver X receptors (LXRs), encoded by the nuclear receptor subfamily 1 group H members 2 and 3 (NR1H3 and NR1H2), are master regulators of these pathways, herein we investigated the role of LXR in human and mouse eyes as a function of age and disease and tested the therapeutic potential of targeting LXR. We identified immunopositive LXR fragments in human extracellular early dry AMD lesions and a decrease in LXR expression within the retinal pigment epithelium (RPE) as a function of age. Aged mice lacking LXR presented with isoform-dependent ocular pathologies. Specifically, loss of the Nr1h3 isoform resulted in pathobiologies aligned with AMD, supported by compromised visual function, accumulation of native and oxidized lipids in the outer retina, and upregulation of ocular inflammatory cytokines, while absence of Nr1h2 was associated with ocular lipoidal degeneration. LXR activation not only ameliorated lipid accumulation and oxidant-induced injury in RPE cells but also decreased ocular inflammatory markers and lipid deposition in a mouse model, thereby providing translational support for pursuing LXR-active pharmaceuticals as potential therapies for dry AMD

Bone Marrow Transplantation Transfers Age-Related Susceptibility to Neovascular Remodeling in Murine Laser- Induced Choroidal Neovascularization

Citation: Espinosa-Heidmann DG, Malek G, Mettu PS, et al. Bone marrow transplantation transfers age-related susceptibility to neovascular remodeling in murine laser-induced choroidal neovascularization. Invest Ophthalmol Vis Sci. 2013;54:7439-7449. DOI:10.1167/iovs.13-12546 PURPOSE. Neovascular remodeling (NVR), the progression of small capillaries into large-caliber arterioles with perivascular fibrosis, represents a major therapeutic challenge in neovascular age-related macular degeneration (AMD). Neovascular remodeling occurs after laser-induced choroidal neovascularization (CNV) in aged but not young mice. Additionally, bone marrowderived cells, including macrophages, endothelial precursor cells, and mesenchymal precursor cells, contribute to CNV severity. In this study, we investigated the impact of aged bone marrow transplantation (BMT) on the degree of fibrosis, size, and vascular morphology of CNV lesions in a mouse model of laser-induced CNV. METHODS. Young (2 months) and old (16 months) mice were transplanted with green fluorescent protein (GFP)-labeled bone marrow isolated from either young or old donors. Laser CNV was induced 1 month following transplant, and eyes were analyzed via choroidal flat mounts and immunohistochemistry 1 month postlaser. The identity of cells infiltrating CNV lesions was determined using specific markers for the labeled transplanted cells (GFPþ), macrophages (F4/80þ), perivascular mesenchymal-derived cells (smooth muscle actin, SMAþ), and endothelial cells (CD31þ). RESULTS. Bone marrow transplantation from aged mice transferred susceptibility to NVR into young recipients. Inversely, transplantation of young marrow into old mice prevented NVR, preserving small size and minimal fibrosis. Mice with NVR demonstrated a greater relative contribution of marrow-derived SMAþ perivascular mesenchymal cells as compared to other cells. CONCLUSIONS. Our findings indicate that the status of bone marrow is an important determining factor of neovascular severity. Furthermore, we find that perivascular mesenchymal cells, rather than endothelial cells, derived from aged bone marrow may contribute to increased CNV severity in this murine model of experimental neovascularization

Correction: Peavey et al. Nuclear Receptor Atlases of Choroidal Tissues Reveal Candidate Receptors Associated with Age-Related Macular Degeneration. Cells 2022, 11, 2386

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Does senescence play a role in age-related macular degeneration?

Advanced age is the most established risk factor for developing age-related macular degeneration (AMD), one of the leading causes of visual impairment in the elderly, in Western and developed countries. Similarly, after middle age, there is an exponential increase in pathologic molecular and cellular events that can induce senescence, traditionally defined as an irreversible loss of the cells ability to divide and most recently reported to also occur in select post-mitotic and terminally differentiated cells, such as neurons. Together these facts raise the question as to whether or not cellular senescence, may play a role in the development of AMD. A number of studies have reported the effect of ocular-relevant inducers of senescence using primarily in vitro models of poorly polarized, actively dividing retinal pigment epithelial (RPE) cell lines. However, in interpretating the data, the fidelity of these culture models to the RPE in vivo, must be considered. Fewer studies have explored the presence and/or impact of senescent cells in in vivo models that present with phenotypic features of AMD, leaving this an open field for further investigation. The goal of this review is to discuss current thoughts on the potential role of senescence in AMD development and progression, with consideration of the model systems used and their relevance to human disease

Characterization of Calcium Phosphate Spherical Particles in the Sub–Retinal Pigment Epithelium–Basal Lamina Space in Aged Human Eyes

Purpose: Micrometer-sized spherules formed of hydroxyapatite or whitlockite were identified within extracellular deposits that accumulate in the space between the basal lamina (BL) of retinal pigment epithelium (RPE) and the inner collagenous layer of Bruch’s membrane (sub-RPE–BL space). This investigation aimed to characterize the morphologic features, structure, and distribution of these spherules in aged human eyes with and without clinical indications of age-related macular degeneration (AMD). Design: Experimental study. Participants: Five human eyes with varying degrees of sub-RPE–BL deposits were obtained from the University College London Institute of Ophthalmology and Moorfield’s Eye Hospital Tissue Repository or the Advancing Sight Network. Two eyes were reported as having clinical indications of AMD (age, 76–87 years), whereas 3 were considered healthy (age, 69–91 years). Methods: Cadaveric eyes with sub-RPE–BL deposits were embedded in paraffin wax and sectioned to a thickness of 4-10 μm. Spherules were identified and characterized using high-resolution scanning electron microscopy (SEM), energy-dispersive x-ray spectroscopy, and time-of-flight secondary ion mass spectroscopy. Main Outcome Measures: High-resolution scanning electron micrographs of spherules, the size-frequency distribution of spherules including average diameter, and the distribution of particles across the central-peripheral axis. Elemental maps and time-of-flight secondary ion mass spectra also were obtained. Results: The precipitation of spherules is ubiquitous across the central, mid-peripheral, and far-peripheral axis in aged human eyes. No significant difference was found in the frequency of spherules along this axis. However, statistical analysis indicated that spherules exhibited significantly different sizes in these regions. In-depth analysis revealed that spherules in the sub-RPE–BL space of eyes with clinical signs of AMD were significantly larger (median diameter, 1.64 μm) than those in healthy aged eyes (median diameter, 1.16 μm). Finally, spherules showed great variation in surface topography and internal structure. Conclusions: The precipitation of spherules in the sub-RPE–BL space is ubiquitous across the central–peripheral axis in aged human eyes. However, a marked difference exists in the size and frequency of spherules in eyes with clinical signs of AMD compared to those without, suggesting that the size and frequency of spherules may be associated with AMD