Characterizing novel hippocampal drugs for Alzheimer's disease

 描述（由申请人提供）：阿尔茨海默病（AD）是最常见的人类CNS神经退行性疾病，AD最常见的体征之一是记忆丧失。尽管进行了大量的研究，但没有有效的治疗方法可以改善AD的记忆。过氧化物酶体增殖物激活受体（Peroxisome proliferator-activated receptor，PPAR）是一种调节脂肪酸代谢相关基因的转录因子。虽然海马不代谢脂肪，最近我们已经证明，PPAR γ是组成性表达在海马神经元的核，并令人惊讶地控制钙内流和各种可塑性相关基因的表达，通过CREB的直接转录调控。作为一种核激素受体，PPAR γ需要配体才能转运到细胞核中。由于PPAR γ组成性存在于海马神经元的核中，因此配体也必须组成性存在于海马神经元中。有趣的是，我们从正常小鼠海马提取物中鉴定了三种新的配体（十六酰胺，十八烯酰胺和3-羟基，2，2-二甲基丁酸酯）。在这里，我们想检查这些新的配体在海马中的功能，比较这些配体及其受体PPAR γ在AD患者、轻度认知障碍（MCI）和年龄匹配的无认知障碍的对照组的海马中的水平，并描述这些配体是否通过PPAR γ改善AD动物模型中的记忆和学习。这项拨款提案的积极成果将突出新的海马配体的发现，使我们能够开发基于海马的药物，以增强突触可塑性，并保护包括AD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.