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.

描述(申请人提供)：阿尔茨海默病(AD)是美国主要的死亡原因之一，表明缺乏预防疾病发展的治疗方法。阿尔茨海默病死亡率的持续上升表明迫切需要发现新的药物，并进一步确定治疗潜力的新分子靶点。许多报告证实了AD和糖尿病之间的直接病理联系，这突显了糖尿病对AD发展的贡献。噻唑烷二酮类(TZD)是胰岛素增敏的过氧化体增殖物激活受体γ(PPARγ)激动剂，已被认为是治疗AD患者记忆的有效药物。然而，确切的信号机制仍然相对未知。尽管目前可用的PPARγ激动剂显示出改善AD记忆缺陷的前景，但血脑屏障通透性差导致脑内生物利用度不足，需要在慢性时间框架内高剂量服用 与心肌梗死发病率增加有关。本研究的创新之处在于开发了具有高血脑屏障通透性的新型选择性PPARγ调节剂。这些选择性的PPARγ调节剂被用作工具，以更好地了解中央PPARγ激活如何改变AD动物模型的突触可塑性和认知，而不会对心脏产生有害的副作用。我们已经发现了一种新的信号机制，在这种机制中，PPARγ转录调节神经营养因子BDNF的表达增加，这是已知的诱导突触发生和改善记忆巩固的机制。虽然我们的先导化合物改善记忆缺陷和增加突触后受体表达的初步数据是在2型糖尿病(db/db)小鼠模型中进行的，但在当前的提案中，这些发现将扩展到3xTg-Ad小鼠模型。我们的中心假设将测试我们的先导化合物在3xTg-AD小鼠身上比目前的TZDS更好地改善阿尔茨海默病相关的认知缺陷和病理改变，目的如下：(化合物9)1.比较化合物9和Pio在改善3xTg-AD小鼠记忆缺陷和突触可塑性方面的有益效果。2.评估化合物9与Pio相比如何挽救认知缺陷和病理的可能机制。我们预计，对这些化合物的进一步评估将导致增加识别分子靶点的知识库，从而改善与AD相关的记忆缺陷。这项研究的发现将推进知识基础和有益的机制洞察PPARγ对抗AD的作用模式。

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.