Decreased thickness and integrity of the macular elastic layer of Bruch’s membrane correspond to the distribution of lesions associated with age-related macular degeneration

Chong, Nhv; Keonin, Jason; Luthert, Philip J; Frennesson, Christina; Weingeist, David M.; Wolf, Robert L.; Mullins, Robert F.; Hageman, Gregory S.

doi:10.1016/j.ajo.2005.04.005

Cited by 59 publications

(92 citation statements)

References 51 publications

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“…Clinical disorders with breaks in the Bruch membrane, such as pathologic myopia, trauma, pseudoxanthoma elasticum, and histoplasmosis, show an increased incidence of CNV. Furthermore, recent study has suggested that the integrity and thickness of the macular elastic layer of the Bruch membrane in patients with CNV related to AMD were significantly lower as compared with that in unaffected and age-matched controls (53). The second possibility is that the 27-month-old mice are not senescent enough to mimic aged human subjects.…”

Section: Figurementioning

confidence: 89%

The potential role of amyloid in the pathogenesis of age-related macular degeneration

Yoshida

Ohno‐Matsui

Ichinose

et al. 2005

Journal of Clinical Investigation

195

153

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Drusen are extracellular deposits that lie beneath the retinal pigment epithelium (RPE) and are the earliest signs of age-related macular degeneration (AMD). Recent proteome analysis demonstrated that amyloid β (Aβ) deposition was specific to drusen from eyes with AMD. To work toward a molecular understanding of the development of AMD from drusen, we investigated the effect of Aβ on cultured human RPE cells as well as ocular findings in neprilysin gene-disrupted mice, which leads to an increased deposition Aβ. The results showed that Aβ treatment induced a marked increase in VEGF as well as a marked decrease in pigment epitheliumderived factor (PEDF). Conditioned media from Aβ-exposed RPE cells caused a dramatic increase in tubular formation by human umbilical vein endothelial cells. Light microscopy of senescent neprilysin gene-disrupted mice showed an increased number of degenerated RPE cells with vacuoles. Electron microscopy revealed basal laminar and linear deposits beneath the RPE layer, but we did not observe choroidal neovascularization (CNV). The present study demonstrates that Aβ accumulation affects the balance between VEGF and PEDF in the RPE, and an accumulation of Aβ reproduces features characteristic of human AMD, such as RPE atrophy and basal deposit formation. Some other factors, such as breakdown of integrity of Bruch membrane, might be necessary to induce CNV of AMD.

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Section: Figurementioning

confidence: 89%

The potential role of amyloid in the pathogenesis of age-related macular degeneration

Yoshida

Ohno‐Matsui

Ichinose

et al. 2005

Journal of Clinical Investigation

195

153

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“…Specifically, it is likely that patients with AMD have a stiffer, less compliant arterial vasculature leading to the eye, and that the loss of compliance of the large blood vessels is due to age-related degenerative changes in collagen and elastin. 13 A recent histopathological study 14 has shown that in patients with AMD, the macular Bruch's membrane, comprised of inner and outer collagen-rich layers flanking a central layer of elastin and elastin-associated proteins, is thinner and more porous than in agematched controls. The increased porosity is due to larger gaps in the elastin layer in eyes with AMD.…”

Section: Discussionmentioning

confidence: 99%

Retinal haemodynamics in patients with age-related macular degeneration

Satô

Feke

Menke

et al. 2005

Eye

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Objective To investigate whether there is an association between the magnitude of retinal haemodynamic abnormalities in patients with age-related macular degeneration (AMD) and the degree of severity of the AMD. Methods A retinal laser Doppler system (Canon CLBF 100) was used to measure retinal arterial haemodynamic parameters in 25 eyes of 25 patients with AMD and nine eyes of nine age-matched control subjects. Severity of AMD was classified into Mild (n ¼ 11), Moderate (n ¼ 7), or Severe (n ¼ 7). The pulsatility ratio (PR), the pulsatility index (PI), and the resistivity index (RI) were determined. Results PR, PI, and RI in the patients with AMD were each significantly higher than in the control group, and increased monotonically with increasing severity of AMD. However, there were no differences in mean blood velocity, arterial diameter, or blood flow rate among the groups. This suggests that the increased blood flow pulsatility in the retinal arteries of the eyes with AMD is not due to increased distal vascular resistance, but instead is likely due to a loss of compliance in the arterial vasculature leading to the eye. Conclusion Our results suggest that an increasing vascular rigidity in the systemic arterial circulation is directly associated with an increasing severity of AMD.

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“…This finding suggests that fibulin-5 may participate in basal deposit formation in AMD. Interestingly, the distribution of fibulin-5 was more widespread than that of elastin, which appears on immunohistochemistry as a narrow band (see for example, Chong et al, 2005).…”

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confidence: 99%

Fibulin-5 distribution in human eyes: Relevance to age-related macular degeneration

Mullins¹,

Olvera²,

Clark³

et al. 2007

Experimental Eye Research

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Fibulin-5 is an extracellular matrix glycoprotein that participates in elastogenesis. Mutations in the gene for fibulin-5 have been found to be associated with age-related macular degeneration. Little is known, however, about the expression of this gene in normal eyes or eyes with age-related macular degeneration. In this study we evaluated the expression of the fibulin-5 protein in human donor eyes and localized this protein to Bruch's membrane and the intercapillary pillars of the choriocapillaris in normal eyes. In eyes with age-related macular degeneration, fibulin-5 was localized to pathologic basal deposits beneath the retinal pigment epithelium as well as some small drusen. These results suggest that fibulin-5 may promote extracellular deposit formation in macular degeneration. Keywordsage-related macular degeneration; fibulins; extracellular matrix; Bruch's membrane Bruch's membrane is a complex structure composed of 5 layers of extracellular matrix located between the retinal pigment epithelium (RPE) and the choriocapillaris. Bruch's membrane plays a number of important roles in normal retinal physiology. Oxygen, glucose and growth factors derived from the choroidal vasculature must pass through this tissue to supply the photoreceptor cells and RPE, while wastes derived from these highly metabolically active cells must pass in the opposite direction to be removed by the choroidal vasculature. In addition, Bruch's membrane is a site for RPE adhesion and also serves as a barrier to neovascularization, as ruptures in this structure are associated with abnormal angiogenesis from the choroid into the retina.During normal aging, and especially in age-related macular degeneration (AMD), Bruch's membrane undergoes morphological changes with extracellular deposit formation. Deposits in Bruch's membrane include drusen and basal deposits (flat and diffuse deposits beneath the Send correspondence to:

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Decreased thickness and integrity of the macular elastic layer of Bruch’s membrane correspond to the distribution of lesions associated with age-related macular degeneration

Cited by 59 publications

References 51 publications

The potential role of amyloid in the pathogenesis of age-related macular degeneration

The potential role of amyloid in the pathogenesis of age-related macular degeneration

Retinal haemodynamics in patients with age-related macular degeneration

Fibulin-5 distribution in human eyes: Relevance to age-related macular degeneration

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