Oral Epigallocatechin Gallate (EGCG) for Treatment of Alzheimer's Disease Induced Hearing Loss

当前摘要--补编 最近的数据表明阿尔茨海默病和听力损失之间存在联系。有报道称， 耳蜗内淀粉样蛋白β(Aβ)的沉积可能是听力损失的原因。在转基因小鼠模型中 阿尔茨海默病，已有研究表明听力丧失与耳蜗中的β沉积有关。 我们实验室以前的研究表明，Aβ增加了钙离子和炎症标志物。 原代培养大鼠神经元。此外，我们观察到3xTg模型小鼠的皮质组织(也 3xTg-AD模型)增加了肿瘤坏死因子-α水平。我们推测类似的事件也发生在 阿尔茨海默病小鼠模型的耳蜗会导致这些小鼠的听力损失。因为我们的 我们认为，目前的RO1建议是基于耳蜗炎会导致听力损失的假设 阿尔茨海默病补助金在最初拨款的一般范围内。因此， 附录中概述的实验将检验阿尔茨海默氏症转基因小鼠表现出的时间- 与A-β在耳蜗内积聚有关的依赖性听力损失。《特定目标1》将探索 出生后0~6月龄5XFAD小鼠模型的年龄相关性听力损失 在此期间，这些小鼠显示出大脑中的淀粉样蛋白沉积和认知缺陷。各种炎症性和 凋亡标记物将通过免疫组织化学和实时定量聚合酶链式反应检测。特定目标2将 检查口服表没食子儿茶素没食子酸酯(EGCG)的效果，EGCG是一种具有抗氧化和抗衰老作用的天然产品 炎症特性，对此模型小鼠听力损失的发展。这种药有希望治疗 阿尔茨海默病的临床前试验中的治疗。EGCG目前正在当前的父RO1中使用 治疗顺铂耳毒性。它被证明对这一适应症特别有效。我们相信这一产品经得起考验 在这些动物中提供听力保护是一个很好的机会，最终在遭受 阿尔茨海默氏症导致的听力损失。

Current Abstract - Supplement Recent data suggest an association between Alzheimer’s disease and hearing loss. Some reports suggest that amyloid β (Aβ) deposition in the cochlea could account for the hearing loss. In transgenic mouse models of Alzheimer’s disease, it has been shown that the loss of hearing was associated with Aβ deposition in the cochlea. Previous studies from our laboratory indicate that Aβ increases Ca2+ and increased inflammatory markers in primary neuron cultures from rats. In addition, we observed that cortical tissues from 3xTg mouse model (also known as 3xTg-AD model) have increased levels of TNF-α. We speculate that a similar event occurs in the cochleae of Alzheimer’s disease mouse models which could contribute to hearing loss in these mice. Since our current RO1 proposal is based on the hypothesis that cochlear inflammation produces hearing loss, we believe that a Supplement on Alzheimer’s disease is within the general scope of the original grant. Therefore, experiments outlined in the supplement will test the hypothesis that Alzheimer’s transgenic mice show a time- dependent loss of hearing which is associated with Aβ accumulation in the cochlea. Specific aim 1 will explore the age-dependent loss of hearing in the 5XFAD mouse model covering the postnatal period 0 to 6 months during which these mice show amyloid deposition in the brain and cognitive deficits. Various inflammatory and apoptotic markers will be examined by immunohistochemical and real time PCR assays. Specific aim 2 will examine the effect of oral epigallocatechin gallate (EGCG), a natural product with antioxidant and anti- inflammatory properties, on the development of hearing loss in this mouse model. This drug shows promise for treatment of Alzheimer’s disease in preclinical trials. EGCG is currently being used in the current parent RO1 to treat cisplatin ototoxicity. It was shown to particularly effective for this indication. We believe this product stands a good chance in providing hearing protection in these animals and ultimately in humans suffering from Alzheimer’s-induced hearing loss.