Cyclohexanehexol Therapy in Transgenic Models of Alzheimer's Disease

阿尔茨海默病转基因模型中的环己烷六醇疗法

• 批准号: 8310946
• 负责人: ALPASLAN DEDEOGLU
• 金额: $ 38.19万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8310946
• 关键词: Adverse effects; Affect; Age; Age-Months; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Asses; Behavioral; Biochemical; Biological Markers; Brain; Clinical Trials; Cognitive; Combined Modality Therapy; Dementia; Deposition; Development; Diagnosis; Diagnostic Procedure; Disease; Disease Progression; Dose; Enzyme-Linked Immunosorbent Assay; Flurbiprofen; Future; Genes; Goals; Government; Healthcare; Human; Ibuprofen; Image; Imaging Techniques; Immunohistochemistry; Impaired cognition; In Vitro; Inositol; Isomerism; Life; Longitudinal Studies; Magnetic Resonance Spectroscopy; Measures; Metabolic; Modeling; Monitor; Mus; Neurofibrillary Tangles; Non-Steroidal Anti-Inflammatory Agents; Oral; Pathogenesis; Pathology; Pathway interactions; Peptides; Performance; Pharmaceutical Preparations; Pharmacology; Phase; Play; Population; Prostaglandin-Endoperoxide Synthase; Proteins; Public Health; R-flurbiprofen; Radial; Reporting; Research; Scanning; Senile Plaques; Spectrum Analysis; Techniques; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Intervention; Therapeutic Uses; Time; Tissue Sample; Transgenic Mice; Transgenic Organisms; Water; Western Blotting; abstracting; amyloid precursor protein processing; arm; base; behavior test; cognitive function; cost; design; enantiomer; extracellular; gastrointestinal; immunocytochemistry; improved; in vivo; long term memory; mouse model; neurochemistry; neurofibrillary tangle formation; neurotoxic; neurotoxicity; novel; prevent; prophylactic; protein aggregate; response; scyllo-inositol; tau Proteins; tau-1; thioflavine; transgenic model of alzheimer disease

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.

项目总结/摘要 老年斑含有β淀粉样蛋白（Ass）和神经纤维缠结（NFT）与磷酸化tau蛋白， 阿尔茨海默病（AD）的病理学标志。Ass肽，特别是As 42，被认为在 AD的发病机制。我们发现，布洛芬，一种非甾体抗炎药（NSAID）与Ass 42- 降低作用，减少了新的三重转基因小鼠模型中的Ass沉积、NFT和认知下降， AD（3xTg-AD），发生老年斑和NFT。R-氟比洛芬，NSAID的对映体 氟比洛芬降低了AD转基因小鼠的As 42但缺乏环氧合酶抑制作用， 目前正在进行III期AD临床试验。我们发现口服R-氟比洛芬的耐受性良好， 在转基因小鼠脑中可检测到。环己六醇的异构体Scyllo-inositol抑制Ass寡聚体 形成，并且当口服给药于AD转基因小鼠时，减少Ass聚集和沉积，和 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， 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，不发展NFT，但发展更广泛， 的第二异构体的预防和治疗作用， 环己六醇、肌醇，单独和与R-氟比洛芬组合。我们假设 环己烷己醇将降低Ass的神经毒性，并改善神经化学特征和认知功能。 通过降低Ass 42的寡聚化来提高转基因小鼠的性能， R-氟比洛芬通过完全不同的作用机制减少Ass沉积， 累加治疗效应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水平与使用MRS的鲨肌醇治疗和治疗改善 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， 在小鼠中耐受。本建议的目的是：1）评估，代谢，组织病理学， 口服鲨肌醇或肌醇治疗的双转基因和三转基因小鼠的生物化学和认知特征 在病理学建立之前或之后。将使用对屁股没有影响的手性肌醇 作为对照。将使用径向臂水迷宫和生化和组织学研究行为效应 采用Western blot、ELISA、MRS和定量免疫细胞化学方法研究其作用; 2）评估 用R-氟比洛芬和最有效的环己烷六醇化合物的联合治疗是否 使用目标1中定义的参数，目标1将具有附加的治疗效果。我们还将执行串行 在限定年龄的小鼠上进行MRS以评估组合疗法对代谢谱的纵向效应。 我们拟议的研究将调查诊断方法和潜在的治疗方法，整合疾病的状态 艺术成像，神经病理学和生物化学技术，以帮助设计策略，以预防和治疗AD。