Guo Li, Salt Thomas E, Luong Vy, Wood Nicholas, Cheung William, Maass Annelie, Ferrari Giulio, Russo-Marie Françoise, Sillito Adam M, Cheetham Michael E, Moss Stephen E, Fitzke Frederick W, Cordeiro M Francesca
Glaucoma and Retinal Degeneration Research, University College London Institute of Ophthalmology, Bath Street, London EC1V 9EL, United Kingdom.
Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13444-9. doi: 10.1073/pnas.0703707104. Epub 2007 Aug 7.
The development of the devastating neurodegenerative condition, Alzheimer's disease, is strongly associated with amyloid-beta (Abeta) deposition, neuronal apoptosis, and cell loss. Here, we provide evidence that implicates these same mechanisms in the retinal disease glaucoma, a major cause of irreversible blindness worldwide, previously associated simply with the effects of intraocular pressure. We show that Abeta colocalizes with apoptotic retinal ganglion cells (RGC) in experimental glaucoma and induces significant RGC apoptosis in vivo in a dose- and time-dependent manner. We demonstrate that targeting different components of the Abeta formation and aggregation pathway can effectively reduce glaucomatous RGC apoptosis in vivo, and finally, that combining treatments (triple therapy) is more effective than monotherapy. Our work suggests that targeting the Abeta pathway provides a therapeutic avenue in glaucoma management. Furthermore, our work demonstrates that the combination of agents affecting multiple stages in the Abeta pathway may be the most effective strategy in Abeta-related diseases.
毁灭性神经退行性疾病阿尔茨海默病的发展与β-淀粉样蛋白（Aβ）沉积、神经元凋亡和细胞丢失密切相关。在此，我们提供证据表明，在视网膜疾病青光眼（全球不可逆失明的主要原因，以前仅与眼压的影响相关）中也涉及这些相同机制。我们发现，在实验性青光眼中，Aβ与凋亡的视网膜神经节细胞（RGC）共定位，并在体内以剂量和时间依赖性方式诱导显著的RGC凋亡。我们证明，靶向Aβ形成和聚集途径的不同成分可有效减少体内青光眼性RGC凋亡，最后，联合治疗（三联疗法）比单一疗法更有效。我们的工作表明，靶向Aβ途径为青光眼治疗提供了一条途径。此外，我们的工作表明，影响Aβ途径多个阶段的药物联合使用可能是Aβ相关疾病中最有效的策略。
