During Glaucoma, α2-Macroglobulin Accumulates in Aqueous Humor and Binds to Nerve Growth Factor, Neutralizing Neuroprotection
During Glaucoma, α2-Macroglobulin Accumulates in Aqueous Humor and Binds to Nerve Growth Factor, Neutralizing Neuroprotection
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DOI：
10.1167/iovs.10-6691
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发表时间：
2011-07-01
影响因子：
4.4
通讯作者：
Saragovi, H. Uri
中科院分区：
文献类型：
--
作者：
Bai, Yujing;Sivori, Delia;Saragovi, H. Uri
目的.青光眼是由视网膜神经节细胞（RGC）的慢性和进行性死亡引起的视神经病变，导致不可逆的失明。高眼压是一个主要的危险因素，但RGC的死亡往往在高眼压正常化后继续，并且可以在正常张力下发生。在啮齿动物和人类中，连续的RGC死亡与神经毒性蛋白（如TNF-α）的局部上调有关。在青光眼大鼠模型中，高眼压也上调了α 2-巨球蛋白的表达，这是神经毒性的。视网膜中α 2-巨球蛋白的上调是长期存在的，甚至在药物降低高IOP后也是如此。α 2-巨球蛋白作为一种可能的生物标志物在人类青光眼中进行了检查，并寻求一种可能的神经毒性作用机制。对从房水（人和大鼠）和视网膜（大鼠）获得的样品中的α 2-巨球蛋白进行定量Western印迹。使用离体神经元存活测定和使用表面等离子体共振的神经生长因子-α 2-巨球蛋白结合研究。在大鼠青光眼模型的房水中，以及在人类青光眼患者的房水中，可溶性α 2-巨球蛋白蛋白的增加也存在，但在白内障患者中不存在。α 2-巨球蛋白具有神经毒性的机制之一是通过TrkA受体抑制神经生长因子的神经保护活性。这项工作进一步证明了RGC死亡的潜在新机制和青光眼的潜在生物标志物或治疗靶点。（Invest Ophthalmol维斯科学。2011; 52：5260-5265）DOI：10.1167/iovs.10-6691
PURPOSE. Glaucoma is an optic neuropathy caused by the chronic and progressive death of retinal ganglion cells (RGCs), resulting in irreversible blindness. Ocular hypertension is a major risk factor, but RGC death often continues after ocular hypertension is normalized, and can take place with normal tension. Continuous RGC death was related in rodents and humans to the local upregulation of neurotoxic proteins, such as TNF-alpha. In rat models of glaucoma, ocular hypertension also upregulates the expression of alpha 2-macroglobulin, which is neurotoxic. alpha 2-macroglobulin upregulation in the retina is long-lived, even after high IOP is reduced with medication. alpha 2-macroglobulin is examined as a possible biomarker in human glaucoma, and a possible neurotoxic mechanism of action is sought.METHODS. Quantitative Western blotting of alpha 2-macroglobulin in samples obtained from aqueous humor (human and rat) and retina (rat) was conducted. Ex vivo neuronal survival assays and nerve growth factor-alpha 2-macroglobulin binding studies using surface plasmon resonance were used.RESULTS. Increased soluble alpha 2-macroglobulin protein is also present in the aqueous humor in a rat glaucoma model, as well as in the aqueous humor of human glaucoma patients but not in cataract patients. One mechanism by which alpha 2-macroglobulin is neurotoxic is by inhibiting the neuroprotective activity of nerve growth factor via TrkA receptors.CONCLUSIONS. This work further documents a potential novel mechanism of RGC death and a potential biomarker or therapeutic target for glaucoma. (Invest Ophthalmol Vis Sci. 2011; 52:5260-5265) DOI: 10.1167/iovs.10-6691