Characterizing novel hippocampal drugs for Alzheimer's disease

 描述(申请人提供)：阿尔茨海默病(AD)是最常见的人类中枢神经系统退行性疾病，AD最常见的症状之一是记忆力丧失。尽管进行了密集的研究，但还没有有效的治疗方法来改善阿尔茨海默病的记忆。过氧化物酶体增殖物激活受体是一种转录因子，调节与脂肪酸分解代谢有关的基因。虽然海马区不代谢脂肪，但最近我们证明PPAR在海马神经元的胞核中有结构性表达，并通过直接转录调控调控钙内流和多种可塑性相关基因的表达。作为一种核激素受体，PPAR需要配体(S)才能转运到细胞核中。由于PPAR存在于海马神经元的细胞核中，因此其配体也必然存在于海马神经元中。有趣的是，我们从正常小鼠的海马区提取液中鉴定出三种新的配体(十六胺、十八胺和3-羟基，2，2-二甲基丁酸酯)。在这里，我们想要检测这些新的配体在海马区的功能，比较这些配体及其受体PPAR在AD患者、轻度认知障碍和年龄匹配的无认知障碍的对照组的海马区的水平，并描述这些配体是否通过PPAR改善AD动物模型的记忆和学习。这项拨款提案的积极结果将突出发现PPAR的新的海马区配体，使我们能够开发基于海马体的药物，以增强突触可塑性，并保护包括阿尔茨海默病在内的认知障碍的记忆和学习。

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common human neurodegenerative disorder of the CNS and one of the most common signs of AD is memory loss. Despite intense investigations, no effective therapy is available to improve memory in AD. Peroxisome proliferator-activated receptor (PPAR)  is a transcription factor that regulates genes involved in fatty acid catabolism. Although hippocampus does not metabolize fat, recently we have demonstrated that PPAR is constitutively expressed in nuclei of hippocampal neurons and surprisingly controls calcium influx and the expression of various plasticity-related genes via direct transcriptional regulation of CREB. Being a nuclear hormone receptor, PPAR needs ligand(s) for translocation into the nucleus. Because PPAR is constitutively present in nuclei of hippocampal neurons, ligands must be constitutively present in the hippocampal neurons as well. Interestingly, we have identified three novel ligands (Hexadecanamide, Octadecenamide and 3-hydroxy, 2, 2-dimethyl butyrate) from hippocampal extracts of normal mice. Here, we would like to examine functions of these novel ligands in the hippocampus, compare levels of these ligands and their receptor PPAR in the hippocampus of patients with AD, mild cognitive impairment (MCI) and age-matched controls with no cognitive impairment, and delineate whether these ligands improve memory and learning in an animal model of AD via PPAR. A positive outcome of this grant proposal will highlight the discovery of novel hippocampal ligands of PPAR, allowing us to develop hippocampus-based drugs to enhance synaptic plasticity and protect memory and learning in cognitive disorders including AD.