scholarly journals Saponin-Mediated Rejuvenation of Bruch’s Membrane: A New Strategy for Intervention in Dry Age-Related Macular Degeneration (AMD)

2021 ◽  
Author(s):  
Yunhee Lee ◽  
Eun Jung Ahn ◽  
Ali Hussain
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Bruch's Membrane ◽  
Bruch’S Membrane ◽  
Age Related ◽  
New Strategy ◽  
The Matrix ◽  
Dry Amd ◽  
Underlying Mechanisms

At present, there is no treatment modality for the vast majority of patients with dry AMD. The pathophysiology of AMD is complex but current evidence suggests that abnormal ageing of Bruch’s membrane imparts a metabolic insult to the retinal pigment epithelium (RPE) and photoreceptor cells that leads eventually to the inflammatory-mediated death of these cells. Underlying mechanisms contributing to the pathology of Bruch’s membrane include the accumulation of ‘debris’ and malfunction of the matrix metalloproteinase (MMP) system resulting in diminished metabolic support of the retina and inefficient removal of toxic pro-inflammatory mediators. Saponins are amphipathic molecules that have a hydrophobic tri-terpenoid lipid region and hydrophilic glycosidic chains that allow for the dispersion of these deposits in Bruch’s and re-activation of the MMP system leading to a 2-fold improvement in the transport properties of the membrane. Such an intervention is expected to improve the bi-directional exchange of nutrients and waste products, thereby slowing the progression of dry AMD. This will be the first drug-based interventionist possibility to address dry AMD.

Bruch’s membrane pathology: A mechanistic perspective

2020 ◽  
Vol 30 (6) ◽  
pp. 1195-1206 ◽  
Author(s):  
Aishwarya Murali ◽  
Subramanian Krishnakumar ◽  
Anuradha Subramanian ◽  
Sowmya Parameswaran
Keyword(s):  
Extracellular Matrix ◽  
Retinal Pigment Epithelium ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Vital Role ◽  
Age Related Macular Degeneration ◽  
Ocular Diseases ◽  
Bruch's Membrane ◽  
Bruch’S Membrane ◽  
Age Related

Bruch’s membrane, an extracellular matrix located between the retinal pigment epithelium and the choroid, plays a vital role as structural and functional support to the retinal pigment epithelium. Dysfunction of Bruch’s membrane in both age-related macular degeneration and other ocular diseases is caused mostly by extracellular matrix degeneration, deposit formation, and angiogenesis. Although these factors are dealt in greater detail with respect to the cells that are degenerated such as the retinal pigment epithelium and the endothelial cells, the pathology involving the Bruch’s membrane is often underrated. Since in most of the macular degenerations early degenerative changes are also observed in the Bruch’s membrane, addressing only the cellular component without the underlying membrane will not yield an ideal clinical benefit. This review aims to discuss the factors and the mechanisms affecting the integrity of the Bruch’s membrane, which would aid in developing an effective therapy for these pathologies.

scholarly journals Genetic LAMP2 deficiency accelerates the age-associated formation of basal laminar deposits in the retina

2019 ◽  
Vol 116 (47) ◽  
pp. 23724-23734 ◽  
Author(s):  
Shoji Notomi ◽  
Kenji Ishihara ◽  
Nikolaos E. Efstathiou ◽  
Jong-Jer Lee ◽  
Toshio Hisatomi ◽  
...  
Keyword(s):  
Basal Lamina ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Critical Role ◽  
Age Related Macular Degeneration ◽  
Bruch's Membrane ◽  
Bruch’S Membrane ◽  
Rpe Cells ◽  
Age Related ◽  
Deficient Mice

The early stages of age-related macular degeneration (AMD) are characterized by the accumulation of basal laminar deposits (BLamDs). The mechanism for BLamDs accumulating between the retinal pigment epithelium (RPE) and its basal lamina remains elusive. Here we examined the role in AMD of lysosome-associated membrane protein-2 (LAMP2), a glycoprotein that plays a critical role in lysosomal biogenesis and maturation of autophagosomes/phagosomes. LAMP2 was preferentially expressed by RPE cells, and its expression declined with age. Deletion of the Lamp2 gene in mice resulted in age-dependent autofluorescence abnormalities of the fundus, thickening of Bruch’s membrane, and the formation of BLamDs, resembling histopathological changes occurring in AMD. Moreover, LAMP2-deficient mice developed molecular signatures similar to those found in human AMD—namely, the accumulation of APOE, APOA1, clusterin, and vitronectin—adjacent to BLamDs. In contrast, collagen 4, laminin, and fibronectin, which are extracellular matrix proteins constituting RPE basal lamina and Bruch’s membrane were reduced in Lamp2 knockout (KO) mice. Mechanistically, retarded phagocytic degradation of photoreceptor outer segments compromised lysosomal degradation and increased exocytosis in LAMP2-deficient RPE cells. The accumulation of BLamDs observed in LAMP2-deficient mice was eventually followed by loss of the RPE and photoreceptors. Finally, we observed loss of LAMP2 expression along with ultramicroscopic features of abnormal phagocytosis and exocytosis in eyes from AMD patients but not from control individuals. Taken together, these results indicate an important role for LAMP2 in RPE function in health and disease, suggesting that LAMP2 reduction may contribute to the formation of BLamDs in AMD.

Tissue engineering of retina and Bruch’s membrane: a review of cells, materials and processes

2018 ◽  
Vol 102 (9) ◽  
pp. 1182-1187 ◽  
Author(s):  
Yong Sheng Edgar Tan ◽  
Pu Jiang Shi ◽  
Chang-J Choo ◽  
Augustinus Laude ◽  
Wai Yee Yeong
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Cell Sheet ◽  
The Elderly ◽  
Age Related Macular Degeneration ◽  
Preclinical Model ◽  
Bruch's Membrane ◽  
Bruch’S Membrane ◽  
Cell Sheet Engineering ◽  
Age Related

The biological, structural and functional configuration of Bruch’s membrane (BM) is significantly relevant to age-related macular degeneration (AMD) and other chorioretinal diseases, and AMD is one of the leading causes of blindness in the elderly worldwide. The configuration may worsen along with the ageing of retinal pigment epithelium and BM that finally leads to AMD. Thus, the scaffold-based tissue-engineered retina provides an innovative alternative for retinal tissue repair. The cell and material requirements for retinal repair are discussed including cell sheet engineering, decellularised membrane and tissue-engineered membranes. Further, the challenges and potential in realising a whole tissue model construct for retinal regeneration are highlighted herein. This review article provides a framework for future development of tissue-engineered retina as a preclinical model and possible treatments for AMD.

scholarly journals Identification of hydroxyapatite spherules provides new insight into subretinal pigment epithelial deposit formation in the aging eye

2015 ◽  
Vol 112 (5) ◽  
pp. 1565-1570 ◽  
Author(s):  
Richard B. Thompson ◽  
Valentina Reffatto ◽  
Jacob G. Bundy ◽  
Elod Kortvely ◽  
Jane M. Flinn ◽  
...  
Keyword(s):  
Fluorescent Dyes ◽  
Secondary Ion Mass Spectrometry ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Complement Factor ◽  
Bruch's Membrane ◽  
Bruch’S Membrane ◽  
Age Related

Accumulation of protein- and lipid-containing deposits external to the retinal pigment epithelium (RPE) is common in the aging eye, and has long been viewed as the hallmark of age-related macular degeneration (AMD). The cause for the accumulation and retention of molecules in the sub-RPE space, however, remains an enigma. Here, we present fluorescence microscopy and X-ray diffraction evidence for the formation of small (0.5–20 μm in diameter), hollow, hydroxyapatite (HAP) spherules in Bruch’s membrane in human eyes. These spherules are distinct in form, placement, and staining from the well-known calcification of the elastin layer of the aging Bruch’s membrane. Secondary ion mass spectrometry (SIMS) imaging confirmed the presence of calcium phosphate in the spherules and identified cholesterol enrichment in their core. Using HAP-selective fluorescent dyes, we show that all types of sub-RPE deposits in the macula, as well as in the periphery, contain numerous HAP spherules. Immunohistochemical labeling for proteins characteristic of sub-RPE deposits, such as complement factor H, vitronectin, and amyloid beta, revealed that HAP spherules were coated with these proteins. HAP spherules were also found outside the sub-RPE deposits, ready to bind proteins at the RPE/choroid interface. Based on these results, we propose a novel mechanism for the growth, and possibly even the formation, of sub-RPE deposits, namely, that the deposit growth and formation begin with the deposition of insoluble HAP shells around naturally occurring, cholesterol-containing extracellular lipid droplets at the RPE/choroid interface; proteins and lipids then attach to these shells, initiating or supporting the growth of sub-RPE deposits.

scholarly journals Lipid accumulation and protein modifications of Bruch’s membrane in age-related macular degeneration

2021 ◽  
Vol 14 (5) ◽  
pp. 766-773
Author(s):  
Li-Hui Meng ◽  
Keyword(s):  
Macular Degeneration ◽  
Lipid Accumulation ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Bruch's Membrane ◽  
Bruch’S Membrane ◽  
Novel Therapy ◽  
Protein Modifications ◽  
Age Related

Age-related macular degeneration (AMD) is a progressive retinal disease, which is the leading cause of blindness in western countries. There is an urgency to establish new therapeutic strategies that could prevent or delay the progression of AMD more efficiently. Until now, the pathogenesis of AMD has remained unclear, limiting the development of the novel therapy. Bruch's membrane (BM) goes through remarkable changes in AMD, playing a significant role during the disease course. The main aim of this review is to present the crucial processes that occur at the level of BM, with special consideration of the lipid accumulation and protein modifications. Besides, some therapies targeted at these molecules and the construction of BM in tissue engineering of retinal pigment epithelium (RPE) cells transplantation were listed. Hopefully, this review may provide a reference for researchers engaged in pathogenesis or management on AMD.

scholarly journals FHL-1 interacts with human RPE cells through the α5β1 integrin and confers protection against oxidative stress

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rawshan Choudhury ◽  
Nadhim Bayatti ◽  
Richard Scharff ◽  
Ewa Szula ◽  
Viranga Tilakaratna ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Fate ◽  
Retinal Pigment ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Bruch's Membrane ◽  
Bruch’S Membrane ◽  
Rpe Cells ◽  
Age Related

AbstractRetinal pigment epithelial (RPE) cells that underlie the neurosensory retina are essential for the maintenance of photoreceptor cells and hence vision. Interactions between the RPE and their basement membrane, i.e. the inner layer of Bruch’s membrane, are essential for RPE cell health and function, but the signals induced by Bruch’s membrane engagement, and their contributions to RPE cell fate determination remain poorly defined. Here, we studied the functional role of the soluble complement regulator and component of Bruch’s membrane, Factor H-like protein 1 (FHL-1). Human primary RPE cells adhered to FHL-1 in a manner that was eliminated by either mutagenesis of the integrin-binding RGD motif in FHL-1 or by using competing antibodies directed against the α5 and β1 integrin subunits. These short-term experiments reveal an immediate protein-integrin interaction that were obtained from primary RPE cells and replicated using the hTERT-RPE1 cell line. Separate, longer term experiments utilising RNAseq analysis of hTERT-RPE1 cells bound to FHL-1, showed an increased expression of the heat-shock protein genes HSPA6, CRYAB, HSPA1A and HSPA1B when compared to cells bound to fibronectin (FN) or laminin (LA). Pathway analysis implicated changes in EIF2 signalling, the unfolded protein response, and mineralocorticoid receptor signalling as putative pathways. Subsequent cell survival assays using H2O2 to induce oxidative stress-induced cell death suggest hTERT-RPE1 cells had significantly greater protection when bound to FHL-1 or LA compared to plastic or FN. These data show a non-canonical role of FHL-1 in protecting RPE cells against oxidative stress and identifies a novel interaction that has implications for ocular diseases such as age-related macular degeneration.

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