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Pharmacological Reports : PR 2006Age-related macular degeneration (AMD) is a disease leading to severe visual loss and legal blindness in the elderly population. Its pathogenesis, likely multifactorial,... (Review)
Review
Age-related macular degeneration (AMD) is a disease leading to severe visual loss and legal blindness in the elderly population. Its pathogenesis, likely multifactorial, involving a complex interaction of metabolic, functional, genetic and environmental factors, remains poorly understood. For these reasons currently used therapeutic approaches are insufficiently effective. Although major abnormalities are seen in four functionally interrelated tissues, i.e., photoreceptors, retinal pigment epithelium (RPE), Bruch's membrane and choriocapillaries, the impairment of RPE cell functions is an early and crucial event in the molecular pathways leading to clinically relevant AMD changes. RPE progressively degenerate, which results in a progressive irreversible degeneration of photoreceptors. Four processes: lipofuscinogenesis, drusogenesis, inflammation and neovascularization, specifically contribute to the development of two forms of AMD, the dry form (non-exudative; geographic atrophy) and the wet form (exudative, neovascular). This paper briefly describes major molecular and cellular events leading to AMD, and presents currently used and new experimental, forthcoming therapeutic strategies.
Topics: Angiogenesis Inhibitors; Antioxidants; Choroidal Neovascularization; Genetic Predisposition to Disease; Humans; Laser Coagulation; Lipofuscin; Macular Degeneration; Photochemotherapy; Pigment Epithelium of Eye; Retinal Drusen
PubMed: 16845209
DOI: No ID Found -
Cell Sep 2021GRN mutations cause frontotemporal dementia (GRN-FTD) due to deficiency in progranulin (PGRN), a lysosomal and secreted protein with unclear function. Here, we found...
GRN mutations cause frontotemporal dementia (GRN-FTD) due to deficiency in progranulin (PGRN), a lysosomal and secreted protein with unclear function. Here, we found that Grn mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid we identified as a pH-dependent PGRN interactor as well as a redox-sensitive enhancer of lysosomal proteolysis and lipolysis. Grn brains also showed an age-dependent, secondary storage of glucocerebrosidase substrate glucosylsphingosine. We investigated a protein replacement strategy by engineering protein transport vehicle (PTV):PGRN-a recombinant protein linking PGRN to a modified Fc domain that binds human transferrin receptor for enhanced CNS biodistribution. PTV:PGRN rescued various Grn phenotypes in primary murine macrophages and human iPSC-derived microglia, including oxidative stress, lysosomal dysfunction, and endomembrane damage. Peripherally delivered PTV:PGRN corrected levels of BMP, glucosylsphingosine, and disease pathology in Grn CNS, including microgliosis, lipofuscinosis, and neuronal damage. PTV:PGRN thus represents a potential biotherapeutic for GRN-FTD.
Topics: Animals; Biological Products; Bone Morphogenetic Proteins; Brain; Endosomes; Female; Frontotemporal Dementia; Gliosis; Humans; Induced Pluripotent Stem Cells; Inflammation; Lipid Metabolism; Lipofuscin; Lysosomal Storage Diseases; Lysosomes; Macrophages; Male; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Nerve Degeneration; Phenotype; Progranulins; Receptors, Immunologic; Receptors, Transferrin; Tissue Distribution
PubMed: 34450028
DOI: 10.1016/j.cell.2021.08.002 -
European Journal of Histochemistry : EJH Feb 2015A brief overview is here provided on lipofuscin and lipofuscin-like substances, with particular reference to their biological significance as well as to their cellular... (Review)
Review
A brief overview is here provided on lipofuscin and lipofuscin-like substances, with particular reference to their biological significance as well as to their cellular origin and pathophysiological role. Special emphasis is also placed on the mutual relationships between lipofuscin and lipofuscin-like lipopigments on one side, and cell autofluorescence on the other.
Topics: Animals; Autophagy; Cells; Fluorescence; Humans; Lipids; Lipofuscin
PubMed: 25820564
DOI: 10.4081/ejh.2015.2485 -
Proceedings of the National Academy of... Nov 2021Lipofuscin granules enclose mixtures of cross-linked proteins and lipids in proportions that depend on the tissue analyzed. Retinal lipofuscin is unique in that it...
Lipofuscin granules enclose mixtures of cross-linked proteins and lipids in proportions that depend on the tissue analyzed. Retinal lipofuscin is unique in that it contains mostly lipids with very little proteins. However, retinal lipofuscin also presents biological and physicochemical characteristics indistinguishable from conventional granules, including indigestibility, tendency to cause lysosome swelling that results in rupture or defective functions, and ability to trigger NLRP3 inflammation, a symptom of low-level disruption of lysosomes. In addition, like conventional lipofuscins, it appears as an autofluorescent pigment, considered toxic waste, and a biomarker of aging. Ocular lipofuscin accumulates in the retinal pigment epithelium (RPE), whereby it interferes with the support of the neuroretina. RPE cell death is the primary cause of blindness in the most prevalent incurable genetic and age-related human disorders, Stargardt disease and age-related macular degeneration (AMD), respectively. Although retinal lipofuscin is directly linked to the cell death of the RPE in Stargardt, the extent to which it contributes to AMD is a matter of debate. Nonetheless, the number of AMD clinical trials that target lipofuscin formation speaks for the potential relevance for AMD as well. Here, we show that retinal lipofuscin triggers an atypical necroptotic cascade, amenable to pharmacological intervention. This pathway is distinct from canonic necroptosis and is instead dependent on the destabilization of lysosomes. We also provide evidence that necroptosis is activated in aged human retinas with AMD. Overall, this cytotoxicity mechanism may offer therapeutic targets and markers for genetic and age-related diseases associated with lipofuscin buildups.
Topics: ATP-Binding Cassette Transporters; Aging; Alcohol Oxidoreductases; Animals; Cell Death; Humans; Intracellular Membranes; Lipofuscin; Lysosomes; Macular Degeneration; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Necroptosis; Retina; Retinal Pigment Epithelium
PubMed: 34782457
DOI: 10.1073/pnas.2100122118 -
Clinical & Experimental Ophthalmology Jul 2021Stargardt disease (STGD1) is an autosomal recessive retinal dystrophy, characterised by bilateral progressive central vision loss and subretinal deposition of... (Review)
Review
Stargardt disease (STGD1) is an autosomal recessive retinal dystrophy, characterised by bilateral progressive central vision loss and subretinal deposition of lipofuscin-like substances. Recent advances in molecular diagnosis and therapeutic options are complemented by the increasing recognition of new multimodal imaging biomarkers that may predict genotype and disease progression. Unique non-invasive imaging features of STDG1 are useful for gene variant interpretation and may even provide insight into the underlying molecular pathophysiology. In addition, pathognomonic imaging features of STGD1 have been used to train neural networks to improve time efficiency in lesion segmentation and disease progression measurements. This review will discuss the role of key imaging modalities, correlate imaging signs across varied STGD1 presentations and illustrate the use of multimodal imaging as an outcome measure in determining the efficacy of emerging STGD1 specific therapies.
Topics: Fluorescein Angiography; Humans; Lipofuscin; Retinal Dystrophies; Stargardt Disease; Tomography, Optical Coherence
PubMed: 34013643
DOI: 10.1111/ceo.13947 -
Scientific Reports Jun 2023Retinal disease accounts significantly for visual impairment and blindness. An important role in the pathophysiology of retinal disease and aging is attributed to...
Retinal disease accounts significantly for visual impairment and blindness. An important role in the pathophysiology of retinal disease and aging is attributed to lipofuscin, a complex of fluorescent metabolites. Fundus autofluorescence (AF) imaging allows non-invasive mapping of lipofuscin and is a key technology to diagnose and monitor retinal disease. However, currently used short-wavelength (SW) excitation light has several limitations, including glare and discomfort during image acquisition, reduced image quality in case of lens opacities, limited visualization of the central retina, and potential retinal light toxicity. Here, we establish a novel imaging modality which uses red excitation light (R-AF) and overcomes these drawbacks. R-AF images are high-quality, high-contrast fundus images and image interpretation may build on clinical experience due to similar appearance of pathology as on SW-AF images. Additionally, R-AF images may uncover disease features that previously remained undetected. The R-AF signal increases with higher abundance of lipofuscin and does not depend on photopigment bleaching or on the amount of macular pigment. Improved patient comfort, limited effect of cataract on image quality, and lack of safety concerns qualify R-AF for routine clinical monitoring, e.g. for patients with age-related macular degeneration, Stargardt disease, or for quantitative analysis of AF signal intensity.
Topics: Humans; Lipofuscin; Retinal Pigment Epithelium; Macular Degeneration; Fundus Oculi; Retinal Diseases; Optical Imaging; Fluorescein Angiography
PubMed: 37336979
DOI: 10.1038/s41598-023-36217-x -
Nature Communications Nov 2023Engulfment of cellular material and proteins is a key function for microglia, a resident macrophage of the central nervous system (CNS). Among the techniques used to...
Engulfment of cellular material and proteins is a key function for microglia, a resident macrophage of the central nervous system (CNS). Among the techniques used to measure microglial engulfment, confocal light microscopy has been used the most extensively. Here, we show that autofluorescence (AF) likely due to lipofuscin (lipo-AF) and typically associated with aging, can also be detected within microglial lysosomes in the young mouse brain by light microscopy. This lipo-AF signal accumulates first within microglia and it occurs earliest in white versus gray matter. Importantly, in gray matter, lipo-AF signal can confound the interpretation of antibody-labeled synaptic material within microglia in young adult mice. We further show that there is an age-dependent accumulation of lipo-AF inside and outside of microglia, which is not affected by amyloid plaques. We finally implement a robust and cost-effective strategy to quench AF in mouse, marmoset, and human brain tissue.
Topics: Mice; Humans; Animals; Microglia; Lipofuscin; Central Nervous System; Macrophages; Microscopy, Confocal
PubMed: 37923732
DOI: 10.1038/s41467-023-42809-y -
Proceedings of the National Academy of... May 2023Age-related macular degeneration, Stargardt disease, and their mouse model are characterized by accelerated accumulation of the pigment lipofuscin, derived from...
Age-related macular degeneration, Stargardt disease, and their mouse model are characterized by accelerated accumulation of the pigment lipofuscin, derived from photoreceptor disc turnover in the retinal pigment epithelium (RPE); lipofuscin accumulation and retinal degeneration both occur earlier in albino mice. Intravitreal injection of superoxide (O) generators reverses lipofuscin accumulation and rescues retinal pathology, but neither the target nor mechanism is known. Here we show that RPE contains thin multi-lamellar membranes (TLMs) resembling photoreceptor discs, which associate with melanolipofuscin granules in pigmented mice but in albinos are 10-fold more abundant and reside in vacuoles. Genetically over-expressing tyrosinase in albinos generates melanosomes and decreases TLM-related lipofuscin. Intravitreal injection of generators of O or nitric oxide (NO) decreases TLM-related lipofuscin in melanolipofuscin granules of pigmented mice by ~50% in 2 d, but not in albinos. Prompted by evidence that O plus NO creates a dioxetane on melanin that excites its electrons to a high-energy state (termed "chemiexcitation"), we show that exciting electrons directly using a synthetic dioxetane reverses TLM-related lipofuscin even in albinos; quenching the excited-electron energy blocks this reversal. Melanin chemiexcitation assists in safe photoreceptor disc turnover.
Topics: Mice; Animals; Melanins; Lipofuscin; Macular Degeneration; Retina; Retinal Pigment Epithelium; ATP-Binding Cassette Transporters
PubMed: 37155898
DOI: 10.1073/pnas.2216935120 -
Experimental Eye Research Sep 2014The retinal pigment epithelium contains three major types of pigment granules; melanosomes, lipofuscin and melanolipofuscin. Melanosomes in the retinal pigment... (Review)
Review
The retinal pigment epithelium contains three major types of pigment granules; melanosomes, lipofuscin and melanolipofuscin. Melanosomes in the retinal pigment epithelium (RPE) are formed during embryogenesis and mature during early postnatal life while lipofuscin and melanolipofuscin granules accumulate as a function of age. The difficulty in studying the formation and consequences of melanosomes and lipofuscin granules in RPE cell culture is compounded by the fact that these pigment granules do not normally occur in established RPE cell lines and pigment granules are rapidly lost in adult human primary culture. This review will consider options available for overcoming these limitations and permitting the study of melanosomes and lipofuscin in cell culture and will briefly evaluate the advantages and disadvantages of the different protocols.
Topics: Animals; Cells, Cultured; Epithelial Cells; Humans; Lipofuscin; Melanins; Models, Animal; Models, Biological; Retinal Pigment Epithelium
PubMed: 25152361
DOI: 10.1016/j.exer.2014.01.016 -
Expert Opinion on Biological Therapy Oct 2018Stargardt macular dystrophy (STGD1) is a hereditary retinal degeneration that lacks effective treatment options. Gene therapy, stem cell therapy, and pharmacotherapy... (Review)
Review
INTRODUCTION
Stargardt macular dystrophy (STGD1) is a hereditary retinal degeneration that lacks effective treatment options. Gene therapy, stem cell therapy, and pharmacotherapy with visual cycle modulators (VCMs) and complement inhibitors are discussed as potential treatments.
AREAS COVERED
Investigational therapies for STGD1 aim to reduce toxic bisretinoids and lipofuscin in the retina and retinal pigment epithelium (RPE). These agents include C20-D3-vitamin A (ALK-001), isotretinoin, VM200, emixustat, and A1120. Avacincaptad pegol is a C5 complement inhibitor that may reduce inflammation-related RPE damage. Animal models of STGD1 show promising data for these treatments, though proof of efficacy in humans is lacking. Fenretinide and emixustat are VCMs for dry AMD and STGD1 that failed to halt geographic atrophy progression or improve vision in trials for AMD. A1120 prevents retinol transport into RPE and may spare side effects typically seen with VCMs (nyctalopia and chromatopsia). Stem cell transplantation suggests potential biologic plausibility in a phase I/II trial. Gene therapy aims to augment the mutated ABCA4 gene, though results of a phase I/II trial are pending.
EXPERT OPINION
Stem cell transplantation, ABCA4 gene therapy, VCMs, and complement inhibitors offer biologically plausible treatment mechanisms for treatment of STGD1. Further trials are warranted to assess efficacy and safety in humans.
Topics: ATP-Binding Cassette Transporters; Animals; Complement Inactivating Agents; Genetic Therapy; Humans; Lipofuscin; Macular Degeneration; Phenyl Ethers; Propanolamines; Stargardt Disease; Stem Cell Transplantation; Therapies, Investigational
PubMed: 30129371
DOI: 10.1080/14712598.2018.1513486