Cyclohexanehexol Therapy in Transgenic Models of Alzheimer's Disease

描述（由申请人提供）：含有β淀粉样蛋白（A？）和具有磷酸化tau的神经元缠结（NFT）的老年斑是阿尔茨海默病（AD）的病理学标志。Ass肽，特别是A 42，被认为在AD的发病机制中起关键作用。我们发现，布洛芬，一种具有降低A42作用的非甾体抗炎药（NSAID），在一种新的AD（3xTg-AD）三重转基因小鼠模型中减少了Ass沉积，NFT和认知能力下降，该模型同时出现老年斑和NFT。R-氟比洛芬是NSAID氟比洛芬的一种对映异构体，可降低AD转基因小鼠的A42，但缺乏环氧合酶抑制作用，可降低A42负荷，目前正在III期AD临床试验中进行测试。我们发现口服R-氟比洛芬在转基因小鼠脑中具有良好的耐受性和可检测性。环己六醇的异构体Scyllo-inositol抑制A？寡聚体的形成，并且当口服给AD转基因小鼠时，减少A？聚集和沉积，并减少认知能力下降。重要的是，鲨肌醇是无毒的，通常存在于大脑中，并且可以通过磁共振波谱（MRS）检测到。我们建议的一个主要目标是使用3xTg-AD模型和双转基因PSAPP模型，该模型不产生NFT，但产生更广泛和快速的A？沉积，以评估鲨肌醇和环己六醇的第二异构体肌醇单独和与R-氟比洛芬组合的预防和治疗效果。我们假设，环己烷己醇将减少A <$42的神经毒性，并通过减少A <$42的寡聚化来改善转基因小鼠的神经化学特征和认知性能，并且与R-氟比洛芬的联合治疗通过完全不同的作用机制减少A <$沉积，将具有相加的治疗效果。我们的初步研究表明，我们可以检测到3-4倍的增加，在转基因小鼠的大脑中的scyllo-肌醇使用MRS治疗的scyllo-肌醇的水平和治疗改善长期记忆在两个转基因小鼠模型。使用肌醇的初步研究表明，它在小鼠中耐受性良好。本建议的目的是：1）评估，代谢，组织病理学，生物化学和认知的双和三重转基因小鼠的治疗与口服scyllo-或肌醇之前或之后的病理学已经建立。手性肌醇对A无影响，将用作对照。将使用径向臂水迷宫研究行为效应，并将使用蛋白质印迹、ELISA、MRS和定量免疫细胞化学研究生物化学和组织学效应; 2）使用目的1中定义的参数评估R-氟比洛芬和目的1中定义的最有效的环己六醇化合物的联合治疗是否具有累加治疗效应。我们还将对规定年龄的小鼠进行系列MRS，以评估联合治疗对代谢谱的纵向影响。我们拟议的研究将研究诊断方法和潜在的治疗方法，整合最先进的成像，神经病理学和生化技术，以帮助设计预防和治疗AD的策略。公共卫生相关性：阿尔茨海默病是一种无情的渐进性疾病，总是致命的，影响数百万美国老年人的疾病，每年花费美国政府数十亿美元的医疗保健费用。在这项提案中，我们将使用一种表达人类阿尔茨海默病基因的转基因小鼠模型来研究我们如何治疗由于大脑中异常蛋白质积累而导致的病理。我们将在活体小鼠中使用治疗剂，并使用最先进的成像技术监测疾病进展，并将结果与免疫组化结果相关联。这些研究将为未来开发更好的检测和治疗阿尔茨海默病的方法奠定重要基础。

DESCRIPTION (provided by applicant): Senile plaques that contain beta amyloid (A¿) and neurofibrillary tangles (NFT) with phosphorylated tau are the pathological hallmarks of Alzheimer's disease (AD). Ass peptides, especially A¿42, are thought to play a key role in the pathogenesis of AD. We found that ibuprofen, a non-steroidal anti-inflammatory drug (NSAID) with A¿42- lowering effects, reduces Ass deposition, NFT and cognitive decline in a novel triple transgenic mouse model of AD (3xTg-AD) that develops both senile plaques and NFT. R-flurbiprofen, an enantiomer of the NSAID flurbiprofen that lowers A¿42 but lacks cyclooxygenase inhibition reduces A¿ burden in AD transgenic mice and is currently being tested in a phase III AD clinical trial. We found that oral R-flurbiprofen is well tolerated and detectable in transgenic mouse brain. Scyllo-inositol, an isomer of cyclohexanahexol, inhibits A¿ oligomers formation and, when orally administered to AD transgenicyc mice, reduces A¿ aggregation and deposition, and reduces cognitive decline. Importantly, scyllo-inositol is nontoxic, normally present in brain, and can be detected by magnetic resonance spectroscopy (MRS). A major goal of our proposal is to use the 3xTg-AD model and a double transgenic PSAPP model, that does not develop NFT but develops more widespread and rapid A¿ deposition, to assess the prophylactic and therapeutic effects of scyllo-inositol and a second isomer of cyclohexanahexol, myo-inositol, alone and in combination with R-flurbiprofen. We hypothesize that cyclohexanehexols will reduce the neurotoxicity of A¿ and improve the neurochemical profile and cognitive performance of transgenic mice by decreasing the oligomerization of A¿42 and that combination therapy with R-flurbiprofen, which reduces A¿ deposition through an entirely different mechanism of action, will have an additive therapeutic effect. Our preliminary studies show that we can detect a 3-4 fold increase in scyllo-inositol levels in the brains of transgenic mice treated with scyllo-inositol using MRS and that the treatment improves long-term memory in both transgenic mouse models. Preliminary studies using myo-inositol show that it is well tolerated in mice. The aims of the present proposal are: 1) To assess, the metabolic, histopathological, biochemical and cognitive profiles of double and triple transgenic mice treated with oral scyllo- or myo-inositol either before or after pathology has been established. Chiro-inositol, which has no effects on A¿, will be used as a control. Behavioral effects will be studied using radial arm water maze and biochemical and histological effects will be studied using western blot, ELISA, MRS and quantitative immunocytochemistry; 2) To assess whether combination therapy with R-flurbiprofen and the most effective cyclohexanahexol compound defined in aim 1 will have additive therapeutic effects using the parameters defined in aim 1. We will also perform serial MRS on mice at defined ages to assess the longitudinal effects of combination therapy on metabolic profiles. Our proposed research will investigate diagnostic methods and potential therapeutics integrating state of the art imaging, neuropathological and biochemical techniques to help design strategies to prevent and treat AD. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is a relentlessly progressive, invariably fatal, disorder affecting millions of older Americans and costing the U.S. government billions of dollars in health care annually. In this proposal we will use a genetically modified mouse model that expresses human Alzheimer genes to study how we can treat the pathologies that are due to the accumulation of abnormal proteins in the brain. We will use therapeutic agents in living mice and monitor the disease progression with state-of-the-art imaging techniques and correlate findings with immunohistochemical findings. These studies will lay important groundwork for the future development of better approaches to detect and treat Alzheimer's disease.