Development of S-Nitrosothiol-based Therapy for Alzheimer's Disease

描述（由申请人提供）： 阿尔茨海默氏病（AD）是老年人中最常见的痴呆形式，影响约10%的65岁或以上的人，但尚未有延迟或阻止疾病进展的治疗方法。在目前老年人口比例逐渐增加的情况下，AD已成为包括退伍军人在内的老年人的一个重要问题。因此，对这种疾病的研究与退伍军人管理局的使命有关。近年来，新的证据表明，脑血管并发症和局部脑血流受损是AD的致病因素沿着并伴有记忆力减退和行为改变。反过来，这一证据为脑血管功能障碍的早期治疗提供了依据，这对于延迟、减缓或预防AD的发展至关重要。 一氧化氮（NO）在维持血管张力和血流动力学中起着重要作用。目前，游离NO供体，如硝普钠和硝化甘油，正在各种临床环境中使用。然而，释放游离NO的这些NO供体可能不是AD的有效治疗，因为伴随的慢性炎症和氧化应激从这些供体中释放NO以产生有害的过氧亚硝酸盐。 在这里，我们建议评估的治疗潜力GSNO，NO在生物系统中的主要运输形式，用于治疗AD。GSNO能够诱导几种细胞信号转导途径，这些途径是NO通过S-转亚硝基化而不产生游离NO的生物学作用所必需的。此外，GSNO在各种疾病条件下涉及抗炎、抗氧化和血管保护作用。因此，GSNO是一个有前途的候选人作为一个独立的治疗脑血管并发症牵连在AD。作为支持，我们最近观察到GSNO治疗抑制了慢性脑灌注不足的老年大鼠（与迟发性AD相关的血管功能障碍的动物模型）和过度表达人A？的转基因小鼠的炎症反应，也减少了A？积累，改善了受损的学习和记忆表现。在这些数据的基础上，设计了以下具体目标，以提高GSNO在治疗AD中的治疗可靠性，优化药理学参数，并研究药物作用的机制。 具体目标1：建立GSNO治疗与阿尔茨海默病相关的脑血管并发症的疗效和药理学最佳剂量：在此目标下，我们建议优化GSNO治疗与AD病理学发展和进展相关的脑血管并发症的疗效。这些研究将采用两种动物模型：产生高水平A？的转基因小鼠用于早发性AD研究，老年大鼠接受双侧颈总动脉闭塞（BCCAO），这是一种人类轻度认知障碍和相关迟发性AD的临床相关模型。 具体目标二：研究GSNO治疗的机制：GSNO抗炎和血管保护活性的意义：在此目标下，我们提出研究脑微血管内皮细胞中GSNO介导的抗炎和血管保护信号级联的机制。这一目标的重点将是研究细胞信号传导介质的S-亚硝基化，调节炎症介质的基因表达和A？穿过血脑屏障（BBB）的清除。 从这里描述的研究结果应该提供一个更好的了解药理学，生物化学和细胞生物学事件的基础血管病理学的AD，和可能的效用GSNO作为治疗AD的管理。 公共卫生相关性： 阿尔茨海默氏病（AD）是老年人中最常见的痴呆症，影响约10%的65岁或以上的人，目前还没有治疗方法。在我国老年人相对比例逐步提高的现状下，AD已成为我国退伍军人和老年人老龄化的一个重要问题。因此，对这种疾病的研究与退伍军人管理局的整体使命非常相关。有证据表明，AD涉及导致脑血流受损的血管并发症，这反过来表明血管功能障碍的早期干预作为AD治疗的治疗剂将是至关重要的。在这里，我们建议评估的治疗潜力S-亚硝基谷胱甘肽，内源性一氧化氮载体，对脑血管并发症与AD的发展。我们预计，这种方法将导致开发一种新的治疗AD的策略，这将为老年退伍军人和老年人的医疗保健提供益处。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common form of dementia in the elderly, affecting about 10% of those aged 65 or over, but no treatment to delay or halt the progression of the disease is as yet available. Under the present situation where the proportion of the elderly population is progressively increasing, AD has become a significant problem for the elderly citizens including Veterans. Therefore, the study of this disease is relevant to the mission of the Veterans Administration. Recently, new evidences indicate cerebrovascular complications and impaired regional cerebral blood flow as the causative factors in AD along with its associated memory loss and behavioral changes. In turn, this evidence provides the rationale for early treatment of cerebrovascular dysfunction which is critical for delaying, slowing down or preventing the development of AD. Nitric oxide (NO) plays an essential role in the maintenance of vascular tone and hemodynamics. Currently, free NO donors, such as sodium nitroprusside and nitroglycerine, are being used in various clinical settings. However, these NO donors, releasing free NO, may not be an effective treatment for AD because the concomitant chronic inflammation and oxidative stress scavenge free NO from these donors to generate deleterious peroxynitrite. Here, we propose to evaluate the therapeutic potential of GSNO, a major transport form of NO in biological systems, for the treatment of AD. GSNO is able to induce several cell signal transduction pathways that are essential for biological action of NO via S-transnitrosylation without generation of free NO. In addition, GSNO is implicated in anti-inflammatory, anti-oxidant, and vaso-protective effects under various disease conditions. Therefore, GSNO is a promising candidate as a stand-alone therapy for cerebrovascular complications implicated in AD. In support, we have recently observed that GSNO treatment inhibited the inflammatory response and also reduced A¿ accumulation and improved impaired learning and memory performance in aged rats with chronic cerebral hypoperfusion, an animal model for vascular dysfunction associated with late-onset AD, and in transgenic mice over-expressing human A¿. On the basis of these data, the following specific aims are designed to improve therapeutic reliability of GSNO in the treatment of AD, to optimize pharmacological parameters, and to investigate mechanisms underlying the drug action(s). Specific Aim 1: To establish therapeutic efficacy and pharmacological optimal dose of GSNO therapy for cerebrovascular complications associated with Alzheimer's disease: Under this aim, we propose to optimize the efficacy of GSNO treatment against cerebrovascular complications associated with development and progression of AD pathology. Two animal models will be employed for these studies: transgenic mice producing high levels of A¿ for studies of early-onset AD and aged rats received bilateral common carotid artery occlusion (BCCAO), a clinically relevant model for human mild cognitive impairment and associated late-onset AD. Specific Aim 2: To investigate the mechanism(s) underlying GSNO therapy: Implication of anti-inflammatory and vaso-protective activities of GSNO: Under this aim, we propose to investigate the mechanism(s) underlying GSNO mediated anti-inflammatory and vaso-protective signaling cascades in brain micro-vessel endothelial cells. Focus of this aim will be to study the S-nitrosylation of cell signaling mediators regulating gene expression for inflammatory mediators and A¿ clearance across the blood brain barrier (BBB). The results from studies described here should provide a better understanding of pharmacological, biochemical and cell biological events underlying vascular pathology of AD, and the possible utility of GSNO as therapeutics for the management of AD. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the most common dementia in the elderly affecting about 10% of those aged 65 or over, for which no treatment is available yet. Under the present situation where the relative proportion of elderly is progressively increasing, AD has become a significant problem in the aging population of veterans and seniors. Therefore, the study of this disease is very relevant to the overall mission of Veterans Administration. Evidence indicates that AD implicates vascular complications leading to impaired cerebral blood flow, in turn suggesting that early intervention of vascular dysfunction would be critical as therapeutics for AD therapeutics. Here, we propose to evaluate the therapeutic potential of S-nitrosoglutathione, an endogenous nitric oxide carrier, against cerebrovascular complications associated with development of AD. We expect that this approach will lead to the development of a new strategy for the treatment of AD which will provide benefits for the healthcare of elderly Veterans and seniors.