Gene Therapy for Alzheimer's Disease

项目摘要/摘要 氧化损伤和炎症随着我们年龄的增长而积累，是许多 遗传病和与年龄相关的疾病。阿尔茨海默病(AD)和许多其他神经退行性疾病， 在疾病进展的早期表现出氧化损伤和炎症的迹象。很可能是因为 一种蛋白质，β-淀粉样前体蛋白及其切割产物的积累，刺激氧化和 阿尔茨海默病中的炎症，超出了生物体适当调节正常保护性反应的能力。NRF2， 转录因子是生物体激活对异常蛋白质反应的正常机制的一部分。 它调节&gt；100基因，这些基因可以保护人类免受氧化、炎症、外来压力和自噬的侵袭。 然而，在阿尔茨海默病中，Nrf2的活性似乎并没有随着疾病的发展而上调。一 因此，方法是通过使用病毒基因疗法传递Nrf2基因来增强人体的自然反应。 这种方法已经成功地延长了神经变性和急性视神经变性动物模型的视力。 神经损伤。 我们建议在两种情况下测试NRF2减少神经元死亡和行为症状的能力 阿尔茨海默病小鼠模型。将直接用于大脑的病毒载体AAV正在进行测试 因为这种载体正在成为临床应用的一个可行的候选者。两种AD小鼠模型 将测试阿尔茨海默病的不同遗传原因，以确定该策略是否适用于整个疾病 频谱。此外，还将使用几种不同的化验方法来测试不同类型的反应，作为以下指标 功效。如果有效，AAV-Nrf2可能被证明在延长神经元的健康和功能方面有用，不仅在 AD，但也许在其他神经退行性疾病中也表现出炎症和氧化。

PROJECT SUMMARY / ABSTRACT Oxidative damage and inflammation accumulate as we age and are prominent components of many genetic and age-related diseases. Alzheimer’s Disease (AD), and many other neurodegenerative diseases, show signs of oxidative damage and inflammation early in the disease progression. It is likely that the accumulation of a protein, the β-amyloid precursor protein and its cleavage products, stimulates oxidation and inflammation in AD, beyond an organism’s ability to properly regulate the normally protective responses. Nrf2, a transcription factor, is part of an organism’s normal mechanism to activate a response to abnormal proteins. It regulates >100 genes that can be protective of oxidation, inflammation, xenobiotic stress, and autophagy. However, in AD, it appears that the activity of Nrf2 is not upregulated in response to the disease process. One approach is thus to augment the body’s natural response by delivering the Nrf2 gene using viral gene therapy. This approach has been successful in prolonging vision in animal models of neurodegeneration and acute nerve damage. We propose to test the ability of Nrf2 to reduce the neuronal death and behavioral symptoms in two mouse models of AD. The viral vector, AAV, that will be used for delivery directly to the brain, is being tested as this vector is emerging as a viable candidate for clinical applications. Two mouse models of AD with different genetic causes of AD will be tested to determine if the strategy is applicable across the disease spectrum. In addition, several different assays will be used to test different types of responses as indicators of efficacy. If effective, AAV-Nrf2 may prove to be useful in extending neuronal health and function, not only in AD, but perhaps in other neurodegenerative diseases that also exhibit inflammation and oxidaiton.