权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Does ethanol-induced lipid metabolism dysfunction aggravate symptoms of dementia?

乙醇引起的脂质代谢功能障碍是否会加重痴呆症状？

基本信息

批准号：
14570936
负责人：
IKEDA Hiroshi
金额：
$ 2.18万
依托单位：
Sapporo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570936/
关键词：
alcohol dependence Alzheimer's disease annexin IV CREB NF κ-B BDNF ApoE NF-κ アルコール性痴呆脂質代謝異アポトーシスエタノール

项目摘要

Ethanol has been shown to induce apoptosis in normal tissues including neural tissues. It has also reported that ethanol has an aspect of aggravate symptoms of dementia. Our previous studies suggest that the quantitative reduction of certain type of adenylyl cyclase is related to the features of alcohol dependence and Alzheimer's disease indicating that cAMP-mediated signal transduction is disordered in those brains. In the present study, we measured the ethanol-induced cytotoxicity and the quantitative alteration of brain-derived neurotrophic factor(BDNF), which is one of the important target genes of CREB. Using SH-SY5Y cells, it was revealed that the amount of BDNF was decreased by the exposure to ethanol in the cultured cells, whereas the activity of NF κ-B was increased. We next investigated the effects of ethanol on the survival on primary cultured rat cortical neurons and the differentiation of neural stem cells(NSCs). Ethanol exposure decreased the survival of neurons. Both ins … More ulin-like growth factor-1(IGF-1) and BDNF promoted neuronal differentiation of NSCs in a dose-dependent-manner, and the inhibition of NSC differentiation by ethanol was suppressed by IGF-1 and BDNF. Ethanol may inhibit NSC differentiation through alteration of cellular pathways related to neurotrophic factors. Furthermore, the isoform specific effects of apoE on the ethanol-induced cytotoxicity were identified. It was shown that the addition of apoE4 diminish the ethanol-induced cytotoxicity, whereas the presence of neither apoE2 nor apoE3 inhibits the cytotoxicity by the exposure of ethanol. The precise mechanisms of promoting effect of apoE on ethanol-induced cell damage have yet to be clarified and further investigations will be required. However, the present study suggests that the ethanol-induced alterations of second messengers below receptors effect on intracellular transfactors and alternate structure of neural network through expression of genes and intracellular proteins, contributing to the development of cognitive disturbances. To the contrary, induction of differentiation into neurons, recovery of number of neurons and promotion of remodeling of neural network may be applied to the treatment of alcoholism and Alzheimer's disease. It seems possible to broaden our choices of therapeutic strategies by approaching to those illnesses regarding them as a cognitive disorders caused by dysfunctions of lipid metabolism and neural network system. Less

乙醇可诱导包括神经组织在内的正常组织细胞凋亡。也有报道称，乙醇有加重痴呆症状的一面。我们之前的研究表明，某些类型腺苷酸环化酶的定量减少与酒精依赖和阿尔茨海默病的特征有关，表明camp介导的信号转导在这些大脑中紊乱。在本研究中，我们测量了乙醇诱导的细胞毒性和脑源性神经营养因子（BDNF）的定量改变，BDNF是CREB的重要靶基因之一。以SH-SY5Y细胞为研究对象，结果表明乙醇对培养细胞的BDNF含量降低，而NF κ-B活性升高。接下来，我们研究了乙醇对原代培养的大鼠皮质神经元存活和神经干细胞（NSCs）分化的影响。乙醇暴露降低了神经元的存活率。胰岛素样生长因子-1（IGF-1）和BDNF均以剂量依赖性的方式促进NSCs的神经元分化，IGF-1和BDNF可抑制乙醇对NSCs分化的抑制作用。乙醇可能通过改变神经营养因子相关的细胞通路来抑制NSC的分化。此外，还鉴定了载脂蛋白e对乙醇诱导的细胞毒性的异构体特异性作用。结果表明，添加apoE4可降低乙醇诱导的细胞毒性，而apoE2和apoE3均不能抑制乙醇诱导的细胞毒性。apoE促进乙醇诱导的细胞损伤的确切机制尚不清楚，需要进一步的研究。然而，目前的研究表明，乙醇诱导的受体以下第二信使的改变通过基因和细胞内蛋白质的表达影响细胞内转运因子和神经网络结构的改变，从而导致认知障碍的发生。相反，诱导神经元分化、恢复神经元数量和促进神经网络重塑可能适用于酒精中毒和阿尔茨海默病的治疗。将这些疾病视为由脂质代谢和神经网络系统功能障碍引起的认知障碍，似乎可以拓宽我们治疗策略的选择。少