n-3 PUFA改善中枢胰岛素抵抗在阿尔兹海默症防治中的作用及机制研究

Alzheimer’s disease (AD) is the challenging problem for public health worldwide. The currently available AD therapies are mainly targeted on the alleviation of the brain age pigment and neurofibrillary tangle formations, presenting the relative limited treatment efficiencies. Recent studies suggest that the central insulin resistance might the initial and crucial progression factors of AD. Although n-3 polyunsaturated fatty acid (PUFA) plays an important role in maintaining the normal structure and functions of central neurons, the beneficial effects of n-3 PUFA on AD control remain inconclusive, possible due to the confounding factors of dietary backgrounds and intervention methods. Based on the previously identified improving effects of n-3 PUFAs on the insulin sensitivity of peripheral tissues, together with the fat-1 model which can evaluate the objective effect of n-3 PUFA by excluding the dietary confounding factors, we hereby propose and further verify the hypothesis that n-3 PUFA can improve the central insulin resistance and subsequently ameliorate the development and progression of AD. Through the establishment of AD rodent model over-expressing the fat-1 gene, this project is designed to comprehensively assess the effect of n-3 PUFA enrichment on central insulin resistance and AD control from the aspects of neuropathology, animal ethology and molecular biology. Our study is of great significance in further clarifying the effect and mechanism of central insulin resistance on AD, and also provides scientific evidence for the prevention and treatment of AD through the dietary management.

阿尔兹海默症（AD）是世界范围内的重大公共卫生问题。现有的AD治疗以减缓脑内老年斑和神经纤维缠结形成为主，疗效亟待改进。新近研究认为，中枢胰岛素抵抗可能是AD的始发因素及进展关键环节。n-3 PUFA在维持神经元正常结构和功能中起重要作用，然而由于受到膳食本底、干预方式等混杂因素的影响，n-3 PUFA对AD的防治效应迄今尚不明确。结合以往研究发现n-3 PUFA对外周组织胰岛素抵抗的改善效应，本项目运用不受饮食因素干扰的fat-1模型，提出并验证“n-3 PUFA可改善中枢胰岛素抵抗，继而抑制AD发生发展”的研究假说。通过构建过表达fat-1基因的AD动物模型，从行为学、神经病理学、分子生物学三个层面，综合评价以中枢胰岛素敏感性调控为靶点的n-3 PUFA强化在AD防治中的作用。本项目对揭示中枢胰岛素抵抗与AD发生发展的关系及作用机制、指导居民通过膳食营养途径防治AD具有重要意义。

阿尔兹海默症（AD）是世界范围内的重大公共卫生问题。现有的AD治疗以减缓脑内老年斑和神经纤维缠结形成为主，疗效亟待改进。新近研究认为，中枢胰岛素抵抗可能是AD的始发因素及进展关键环节。n-3 PUFA在维持神经元正常结构和功能中起重要作用，然而由于受到膳食本底、干预方式等混杂因素的影响，n-3 PUFA对AD的防治效应迄今尚不明确。结合以往研究发现n-3 PUFA对外周组织胰岛素抵抗的改善效应，本项目运用不受饮食因素干扰的fat-1模型，提出并验证“n-3 PUFA可改善中枢胰岛素抵抗，继而抑制AD发生发展”的研究假说。通过构建过表达fat-1基因的AD动物模型，从行为学、神经病理学、分子生物学三个层面，综合评价以中枢胰岛素敏感性调控为靶点的n-3 PUFA强化在AD防治中的作用。我们的结果显示，fat-1缓解了AD的进展，改善了AD的症状。分子生物实验和蛋白组学实验提示fat-1作用机制涉及胰岛素信号通路调控、炎症反应调控、蛋白修饰调控和脂质代谢调控等主要方面。本项目对揭示中枢胰岛素抵抗与AD发生发展的关系及作用机制、指导居民通过膳食营养途径防治AD具有重要意义。