Novel PPAR-gamma agonist selectively activate the ligand binding domain of PPAR-gamma and improve pathology and memory deficits in a 3xTg-Ad mouse model.

新型 PPAR-gamma 激动剂选择性激活 PPAR-gamma 的配体结合域，改善 3xTg-Ad 小鼠模型的病理和记忆缺陷。

基本信息

批准号：
8890576
负责人：
Rajesh H Amin
金额：
$ 36.2万
依托单位：
AUBURN UNIVERSITY AT AUBURN
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2019-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is one of the leading causes of death in United States, suggesting the lack of therapies to prevent the progression of the disease. Continuous increase in the mortality rate due to AD indicates the urgent need for new drug discovery and further establishing the need for novel molecular targets for therapeutic potential. Many reports verify direct pathological links between AD and diabetes, which highlights the contribution of diabetes to the development of AD. Thiazolidinediones (TZDs) are insulin sensitizing peroxisomal proliferator activating receptor gamma (PPARγ) agonists, have been recognized as promising agents for memory in patients with AD. However the exact signaling mechanism remains relatively unknown. Although currently available PPARγ agonists show promise for improving memory deficits in AD, poor blood brain barrier permeability results in inadequate bio-availability in the brain requiring high dosing with chronic time frames that are associated with increased incidences of myocardial infarction. The innovation of our proposed research is based on the development of novel selective PPARγ modulators with high blood brain barrier permeability. These selective PPARγ modulators are used as tools to better understand how central PPARγ activation alters synaptic plasticity and cognition in animal models of AD without the deleterious side effects on the heart. We have identified a novel signaling mechanism in which PPARγ transcriptionally regulates an increase in expression of the neurotrophin BDNF, which is known to induce synaptogenesis and improve memory consolidation. Although our preliminary data in which our lead compound improves memory deficits and increases post synaptic receptor expression is in a diabetic type 2 (db/db) mouse model will extend these findings into a 3xTg-Ad mouse model in the current proposal. Our central hypothesis will test that our lead compound improves cognitive deficits and pathologies associated from Alzheimer's disease better than current TZDs in a 3x Tg-AD mouse with the following aims: (compound 9) 1. To compare the beneficial effects of compound 9 to Pio on improving memory deficits and synaptic plasticity in the 3xTg-AD mouse. 2. To evaluate possible mechanisms for how compound 9 rescues cognitive deficits and pathologies vs Pio. We expect that further evaluation of these compounds will lead to increased knowledge base for identifying molecular targets that will ameliorate memory deficits associated with AD. Findings from this study will advance the knowledge base and beneficial mechanistic insights into PPARγ modes of action against AD.

描述（由适用提供）：阿尔茨海默氏病（AD）是美国死亡的主要原因之一，表明缺乏预防疾病进展的疗法。由于AD而导致的死亡率的持续增加表明迫切需要进行新的药物发现，并进一步确定需要新的分子靶标的治疗潜力。许多报告验证了AD和糖尿病之间的直接病理联系，这突出了糖尿病对AD发育的贡献。噻唑烷二酮（TZD）是胰岛素敏化过氧化物体增生剂激活受体γ（PPARγ）激动剂，已被认为是AD患者的记忆的承诺药物。但是，确切的信号传导机制仍然相对未知。尽管目前可用的PPARγ激动剂显示了改善AD中记忆的有望，但血脑屏障的渗透性差会导致大脑中的生物可用性不足，需要高剂量的慢性时间范围与心肌基础设施的发生率增加有关。我们提出的研究的创新是基于具有高血脑屏障通透性的新型PPARγ调节剂的发展。这些选择性的PPARγ调节剂被用作更好地了解中央PPARγ激活如何改变AD动物模型中的合成可塑性和认知的工具，而没有对心脏产生有害副作用。我们已经确定了一种新型的信号传导机制，其中PPARγ转录调节了神经营养蛋白BDNF的表达增加，该神经营养蛋白BDNF已知会诱导突触发生并改善记忆巩固。尽管我们的铅化合物改善内存定义并增加突触受体表达的初步数据在糖尿病类型2（db/db）中，小鼠模型将这些发现将这些发现扩展到当前建议中的3xTG-AD小鼠模型中。 Our central hypothesis will test that our lead compound improves cognitive deficiencies and pathologies associated from Alzheimer's disease better than current TZDs in a 3x Tg-AD mouse with the following aims: (compound 9) 1. To compare the beneficial effects of compound 9 to Pio on improving memory deficiencies and synaptic plasticity in the 3xTg-AD mouse. 2。评估化合物9如何反应认知缺陷和病理与PIO的可能机制。我们预计，对这些化合物的进一步评估将导致知识库增加，以识别可以改善与AD相关的记忆的分子靶标。这项研究的发现将提高知识库和对PPARγ作用模式的有益机理见解。