scholarly journals HTRA1, an age-related macular degeneration protease, processes extracellular matrix proteins EFEMP1 and TSP1

Aging Cell ◽  
2018 ◽  
Vol 17 (4) ◽  
pp. e12710 ◽  
Author(s):  
Michael K. Lin ◽  
Jin Yang ◽  
Chun Wei Hsu ◽  
Anuradha Gore ◽  
Alexander G. Bassuk ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Macular Degeneration ◽  
Extracellular Matrix Proteins ◽  
Age Related Macular Degeneration ◽  
Matrix Proteins ◽  
Age Related

scholarly journals Extracellular Matrix Dysfunction in Sorsby Patient-Derived Retinal Pigment Epithelium

2021 ◽  
Author(s):  
Abbi L. Engel ◽  
YeKai Wang ◽  
Thomas Khuu ◽  
Emily Worrall ◽  
Megan A Manson ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Macular Degeneration ◽  
Retinal Pigment ◽  
Critical Role ◽  
Thick Layer ◽  
Age Related Macular Degeneration ◽  
Calcium Deposition ◽  
Breakdown Product ◽  
Metabolomics Data ◽  
Age Related

Sorsby Fundus Dystrophy (SFD) is a rare form of macular degeneration that is clinically similar to age-related macular degeneration (AMD). SFD results from mutations found in the tissue inhibitor of metalloproteinase 3 (TIMP3) gene. TIMP3 is secreted by the retinal pigmented epithelium (RPE) into the underlying Bruch's membrane (BrM), and it plays a critical role in maintaining extracellular matrix (ECM) homeostasis. A characteristic feature of post-mortem SFD globes is a thick layer of sub-RPE deposits overlying a disorganized BrM. Although likely central to the pathogenesis of SFD, no animal models have reproduced this phenotype. We generated induced pluripotent stem cell (iPSC)-derived RPE lines from SFD family members with the S204C TIMP3 mutation and observed that SFD RPE have highly dysregulated ECM and form large basal deposits by ~30 days in culture. The sub-RPE deposits are similar in ultrastructure and composition when compared to SFD family member globes. Mutant TIMP3 correction by CRISPR-Cas9 gene editing in SFD iPSC RPE cells resulted in the reversal of sub-RPE calcium deposition. We found that SFD TIMP3 has decreased inhibition of secreted matrix metalloproteinases. ECM dysfunction substantially impacts cellular metabolism. Targeted metabolomics data showed that intracellular 4-hydroxyproline, a major breakdown product of collagen, is significantly elevated in SFD RPE. Further, SFD RPE also has decreased intracellular reduced glutathione and is more vulnerable to oxidative stress. These findings suggest that key elements of SFD pathology can be recapitulated in culture which may lead to insights into disease mechanisms and potential treatments.

Age-related changes of DRG neuronal attachment to extracellular matrix proteins in vitro

Neuroreport ◽  
1993 ◽  
Vol 4 (6) ◽  
pp. 663-666 ◽  
Author(s):  
Kazunori Sango ◽  
Hidenori Horie ◽  
Shuji Inoue ◽  
Yutaro Takamura ◽  
Toshifumi Takenaka
Keyword(s):  
Extracellular Matrix ◽  
Extracellular Matrix Proteins ◽  
Matrix Proteins ◽  
Age Related ◽  
Age Related Changes

scholarly journals High-density lipoproteins are a potential therapeutic target for age-related macular degeneration

2020 ◽  
Vol 295 (39) ◽  
pp. 13601-13616
Author(s):  
Una L. Kelly ◽  
Daniel Grigsby ◽  
Martha A. Cady ◽  
Michael Landowski ◽  
Nikolai P. Skiba ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Macular Degeneration ◽  
Protein Profile ◽  
High Density ◽  
Age Related Macular Degeneration ◽  
High Density Lipoproteins ◽  
Striking Difference ◽  
High Cholesterol Diet ◽  
Rpe Cells ◽  
Age Related

Strong evidence suggests that dysregulated lipid metabolism involving dysfunction of the retinal pigmented epithelium (RPE) underlies the pathogenesis of age-related macular degeneration (AMD), the leading cause of irreversible blindness in the elderly. A hallmark of AMD is the overproduction of lipid- and protein-rich extracellular deposits that accumulate in the extracellular matrix (Bruch's membrane (BrM)) adjacent to the RPE. We analyzed apolipoprotein A-1 (ApoA-1)-containing lipoproteins isolated from BrM of elderly human donor eyes and found a unique proteome, distinct from high-density lipoprotein (HDL) isolated from donor plasma of the same individuals. The most striking difference is higher concentrations of ApoB and ApoE, which bind to glycosaminoglycans. We hypothesize that this interaction promotes lipoprotein deposition onto BrM glycosaminoglycans, initiating downstream effects that contribute to RPE dysfunction/death. We tested this hypothesis using two potential therapeutic strategies to alter the lipoprotein/protein profile of these extracellular deposits. First, we used short heparan sulfate oligosaccharides to remove lipoproteins already deposited in both the extracellular matrix of RPE cells and aged donor BrM tissue. Second, an ApoA-1 mimetic, 5A peptide, was demonstrated to modulate the composition and concentration of apolipoproteins secreted from primary porcine RPE cells. Significantly, in a mouse model of AMD, this 5A peptide altered the proteomic profile of circulating HDL and ameliorated some of the potentially harmful changes to the protein composition resulting from the high-fat, high-cholesterol diet in this model. Together, these results suggest that targeting HDL interactions with BrM represents a new strategy to slow AMD progression in humans.

scholarly journals Subretinal fibrosis in neovascular age-related macular degeneration: current concepts, therapeutic avenues, and future perspectives

2021 ◽  
Author(s):  
Louis Tenbrock ◽  
Julian Wolf ◽  
Stefaniya Boneva ◽  
Anja Schlecht ◽  
Hansjürgen Agostini ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Molecular Mechanisms ◽  
Clinical Manifestations ◽  
Age Related Macular Degeneration ◽  
Matrix Proteins ◽  
Therapeutic Approaches ◽  
Aggressive Form ◽  
Age Related ◽  
Mammalian Retina ◽  
Subretinal Fibrosis

AbstractAge-related macular degeneration (AMD) is a progressive, degenerative disease of the human retina which in its most aggressive form is associated with the formation of macular neovascularization (MNV) and subretinal fibrosis leading to irreversible blindness. MNVs contain blood vessels as well as infiltrating immune cells, myofibroblasts, and excessive amounts of extracellular matrix proteins such as collagens, fibronectin, and laminin which disrupts retinal function and triggers neurodegeneration. In the mammalian retina, damaged neurons cannot be replaced by tissue regeneration, and subretinal MNV and fibrosis persist and thus fuel degeneration and visual loss. This review provides an overview of subretinal fibrosis in neovascular AMD, by summarizing its clinical manifestations, exploring the current understanding of the underlying cellular and molecular mechanisms and discussing potential therapeutic approaches to inhibit subretinal fibrosis in the future.

scholarly journals Matrix Metalloproteinases in Age-Related Macular Degeneration (AMD)

2020 ◽  
Vol 21 (16) ◽  
pp. 5934
Author(s):  
Luis García-Onrubia ◽  
Fco. Javier Valentín-Bravo ◽  
Rosa M. Coco-Martin ◽  
Rogelio González-Sarmiento ◽  
J. Carlos Pastor ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Matrix Metalloproteinases ◽  
Macular Degeneration ◽  
Vision Loss ◽  
Developed Countries ◽  
Age Related Macular Degeneration ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Bruch's Membrane ◽  
Bruch’S Membrane ◽  
Age Related

Age-related macular degeneration (AMD) is a complex, multifactorial and progressive retinal disease affecting millions of people worldwide. In developed countries, it is the leading cause of vision loss and legal blindness among the elderly. Although the pathogenesis of AMD is still barely understood, recent studies have reported that disorders in the regulation of the extracellular matrix (ECM) play an important role in its etiopathogenesis. The dynamic metabolism of the ECM is closely regulated by matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs). The present review focuses on the crucial processes that occur at the level of the Bruch’s membrane, with special emphasis on MMPs, TIMPs, and the polymorphisms associated with increased susceptibility to AMD development. A systematic literature search was performed, covering the years 1990–2020, using the following keywords: AMD, extracellular matrix, Bruch’s membrane, MMPs, TIMPs, and MMPs polymorphisms in AMD. In both early and advanced AMD, the pathological dynamic changes of ECM structural components are caused by the dysfunction of specific regulators and by the influence of other regulatory systems connected with both genetic and environmental factors. Better insight into the pathological role of MMP/TIMP complexes may lead to the development of new strategies for AMD treatment and prevention.

Age related macular degeneration (ARMD) – pathophysiological and clinical features and therapeutic concepts

2001 ◽  
Vol 58 (1) ◽  
pp. 28-35 ◽  
Author(s):  
Ursula Körner-Stiefbold
Keyword(s):  
Macular Degeneration ◽  
Clinical Features ◽  
Altersbedingte Makuladegeneration ◽  
Age Related Macular Degeneration ◽  
Genetische Faktoren ◽  
Age Related ◽  
Therapeutic Concepts

Die altersbedingte Makuladegeneration (AMD) ist eine der häufigsten Ursachen für einen irreversiblen Visusverlust bei Patienten über 65 Jahre. Nahezu 30% der über 75-Jährigen sind von einer AMD betroffen. Trotz neuer Erkenntnisse in der Grundlagenforschung ist die Ätiologie, zu der auch genetische Faktoren gehören, noch nicht völlig geklärt. Aus diesem Grund sind die Behandlungsmöglichkeiten zum jetzigen Zeitpunkt noch limitiert, so dass man lediglich von Therapieansätzen sprechen kann. Die derzeit zur Verfügung stehenden Möglichkeiten wie medikamentöse, chirurgische und laser- und strahlentherapeutische Maßnahmen werden beschrieben.

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