Cyclohexanehexol Therapy in Transgenic Models of Alzheimer's Disease

项目摘要/摘要 含有β淀粉样蛋白(Ass)和带有磷酸化tau的神经原纤维缠结(NFT)的老年斑是 阿尔茨海默病(AD)的病理特征。ASS多肽，特别是AS42，被认为起着关键作用 在AD的发病机制中起重要作用。我们发现布洛芬是一种非类固醇抗炎药，其AS42- 降低效应，减少Ass沉积，NFT和认知功能下降的新的三重转基因小鼠模型 AD(3xTg-AD)，同时出现老年斑和NFT。非甾体抗炎药对映体R-氟比洛芬 氟比洛芬降低AS42但缺乏环氧合酶抑制可减轻AD转基因小鼠的Ass负担和 目前正在进行第三期AD临床试验。我们发现口服R-氟比洛芬耐受性良好， 在转基因小鼠的大脑中可以检测到。环己醇的异构体-肌醇抑制Ass寡聚体 形成和，当口服给AD转基因小鼠时，减少Ass的聚集和沉积，以及 减少认知衰退。重要的是，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。我们提案的一个主要目标是使用3xTg-AD 模型和双转基因PSAPP模型，该模型不发展NFT，但发展更广泛和 快速ASS沉积，以评价肌醇及其第二异构体的预防和治疗效果 环己醇，肌醇，单独或与R-氟比洛芬联合使用。我们假设 环己醇可降低ASS的神经毒性，改善神经化学特征和认知功能 降低AS42寡聚化及其联合治疗对转基因小鼠的影响 R-氟比洛芬通过一种完全不同的作用机制减少驴的沉积，将有 相加的治疗效果。我们的初步研究表明，我们可以检测到肌醇的3-4倍增加。 利用MRS技术研究肌醇对转基因小鼠脑内水平的影响及其治疗效果 两种转基因小鼠模型的长期记忆。使用肌醇的初步研究表明，它是良好的 对小鼠有耐受性。本提案的目的是：1)评估新陈代谢、组织病理学、 口服肌醇对双转基因和三转基因小鼠的生化和认知功能的影响 在病理学确立之前或之后。将使用对臀部没有影响的肌醇 作为对照。将使用放射状手臂水迷宫以及生化和组织学来研究行为效应 将通过免疫印迹、酶联免疫吸附试验、MRS和定量免疫细胞化学等方法研究这些影响；2)评估 是否与R-氟比洛芬和最有效的环己酮化合物联合治疗 使用目标1中定义的参数，目标1将具有相加的治疗效果。我们还将执行系列 在规定年龄的小鼠上进行MRS，以评估联合治疗对代谢谱的纵向影响。 我们建议的研究将调查诊断方法和潜在的治疗整合状态 艺术成像、神经病理学和生化技术，帮助设计预防和治疗阿尔茨海默病的策略。

Project Summary/Abstract Senile plaques that contain beta amyloid (Ass) and neurofibrillary tangles (NFT) with phosphorylated tau are the pathological hallmarks of Alzheimer's disease (AD). Ass peptides, especially Ass42, are thought to play a key role in the pathogenesis of AD. We found that ibuprofen, a non-steroidal anti-inflammatory drug (NSAID) with Ass42- 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 Ass42 but lacks cyclooxygenase inhibition reduces Ass 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 Ass oligomers formation and, when orally administered to AD transgenicyc mice, reduces Ass 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 Ass 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 Ass and improve the neurochemical profile and cognitive performance of transgenic mice by decreasing the oligomerization of Ass42 and that combination therapy with R-flurbiprofen, which reduces Ass 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 Ass, 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.