The potential role of amyloid β in the pathogenesis of age-related macular degeneration
The potential role of amyloid β in the pathogenesis of age-related macular degeneration
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DOI：
10.1172/jci24635
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发表时间：
2005-10-01
影响因子：
15.9
通讯作者：
Morita, I
中科院分区：
文献类型：
--
作者：
Yoshida, T;Ohno-Matsui, K;Morita, I
Drusen是位于视网膜色素上皮（RPE）下方的细胞外沉积物，是视网膜色素上皮的主要成分。年龄相关性黄斑变性（AMD）的早期迹象。最近的蛋白质组学分析表明，淀粉样蛋白β (A β)沉积是AMD眼部的特异性物质。为了从分子上理解drusen引起的AMD的发展，我们研究了a β对培养的人RPE细胞的影响，以及neprilysin基因破坏小鼠的眼部发现，这导致a β的沉积增加。结果表明，A β处理诱导VEGF显著升高，色素上皮衍生因子（PEDF）显著降低。暴露于A β的RPE细胞的条件培养基引起人脐静脉内皮细胞管状形成的急剧增加。光镜下观察到，衰老的neprilysin基因破坏小鼠的RPE细胞变性增多，并出现空泡。电镜显示基底层流和线状沉积在RPE层下，但我们没有观察到脉络膜新生血管（CNV）。本研究表明，A β的积累影响了RPE中VEGF和PEDF之间的平衡，A β的积累再现了人类AMD的特征，如RPE萎缩和基底沉积形成。一些其他因素，如Bruch膜完整性的破坏，可能是诱发AMD的CNV的必要因素。
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 beta (A beta) 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 A beta on cultured human RPE cells as well as ocular findings in neprilysin gene-disrupted mice, which leads to an increased deposition A beta. The results showed that A beta treatment induced a marked increase in VEGF as well as a marked decrease in pigment epithelium-derived factor (PEDF). Conditioned media from A beta-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 A beta accumulation affects the balance between VEGF and PEDF in the RPE, and an accumulation of A beta 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.