载脂蛋白E通过调控星形胶质细胞来源的松果体素水平参与学习记忆改变的分子机制

It was well known that melatonin level in Alzheimer's disease (AD) serum was significantly lower than controls, and that the circadian rhythm was in disorder. There was intense astrogliosis in astrocytes accompanied by hyperactivation of extracellular signal-regulated kinase (ERK) pathway in the AD brain. However, the relationship between this change and the decline in AD learning and memory ability has not been examined. Our preliminary work showed that cultured rat cortical astrocytes could secrete a certain amount of melatonin. Furthermore, different apolipoprotein E genotypes had different regulation on melatonin from glioma cells. But the molecular mechanism involved was still unclear. We hypothesize that apoE genotype regulates melatonin level from astrocytes through the ERK signaling pathway, and ultimately brings about changes in spatial learning and memory abilities. To verify this hypothesis, in the cellular and molecular level, we investigate, by cell biology and molecular biology methods, how different apoE genotypes, after binding to its receptor LRP, influence the key enzyme NAT for melatonin synthesis, the key enzyme MAOA on melatonin metabolic bypass and melatonin receptor MT1 through the ERK signaling pathway, and ultimately affect melatonin level from astrocytes. Additionally, using ApoE transgenic animal model, we study changes in spatial learning and memory abilities by targeted intervention in the ERK signaling pathway in vivo. This project aims to explore the pathogenesis of AD and provide new basis for finding relevant drug targets and putting forward new therapeutic strategies.

老年性痴呆（AD）患者血清松果体素分泌降低，且生理节律紊乱。AD脑星形胶质细胞增生伴随胞外信号调节激酶（ERK）过度激活，但此改变与AD学习记忆能力下降的关系尚未有研究。我们的前期工作发现大鼠皮层星形胶质细胞可以分泌一定量的松果体素，ApoE基因型对星形胶质细胞来源的松果体素有不同的调节作用，但其分子机制不清。我们推测ApoE基因型通过ERK信号通路调控星形胶质细胞来源的松果体素水平引起空间学习记忆能力的改变。为验证该假说：① 在细胞和分子水平应用细胞生物学、分子生物学等方法研究不同ApoE基因型与其受体LRP结合后通过ERK信号通路影响松果体素合成的关键酶NAT、代谢旁路上的关键酶MAOA及它自身的受体MT1，从而调控松果体素水平；②在ApoE转基因动物在体水平，靶向干预ERK信号通路研究空间学习记忆能力的改变。期望为探讨AD的发病机制、寻找有关的药物靶位以及新的治疗策略提供新的依据。

老年性痴呆（AD）患者血清松果体素分泌降低，且生理节律紊乱，但此改变与AD学习记忆能力下降的关系尚未有研究。我们的前期工作发现大鼠皮层星形胶质细胞可以分泌一定量的松果体素，ApoE基因型对星形胶质细胞来源的松果体素有不同的调节作用，但其分子机制不清。我们推测ApoE基因型通过ERK信号通路调控星形胶质细胞来源的松果体素水平引起空间学习记忆能力的改变；APOE基因型可能与慢性应激相互作用影响小鼠的空间学习记忆能力。为验证该假说，我们首先在细胞和分子水平应用细胞生物学、分子生物学等方法研究了不同ApoE基因型通过ERK信号通路影响松果体素合成的关键酶NAT和代谢旁路上的关键酶MAOA，从而调控松果体素水平。其次，利用APOE转基因鼠模型，发现慢性应激环境对不同ApoE亚型转基因小鼠的行为学和认知功能有一定的改变。最后，发现丰富环境对降低了小鼠的焦虑样行为，有利于小鼠的认知功能。以上研究结果表明，慢性应激影响了不同ApoE亚型转基因小鼠的行为学及认知功能的改变，APOE作为AD的遗传因素与多种环境因素之间复杂的相互作用共同参与了AD的发病机制。