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

乙醇已被证明可以诱导正常组织包括神经组织中的细胞凋亡。据报道，乙醇在一定程度上会加重痴呆症的症状。我们以前的研究表明，某些类型的腺苷环化酶的数量减少与酒精依赖和阿尔茨海默病的特征有关，这表明cAMP介导的信号转导在这些大脑中处于紊乱状态。在本研究中，我们检测了乙醇诱导的细胞毒性和CREB的重要靶基因之一脑源性神经营养因子(BDNF)的定量变化。在SH-SY5Y细胞中，乙醇可使培养细胞中脑源性神经营养因子的含量减少，而神经营养因子κ-B的活性增加。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分化的影响。酒精暴露降低了神经元的存活率。两个INS…更多的胰岛素样生长因子-1(IGF-1)和BDNF以剂量依赖的方式促进神经干细胞的分化，而乙醇对NSC分化的抑制作用则被IGF-1和BDNF抑制。乙醇可能通过改变神经营养因子相关的细胞通路来抑制神经干细胞的分化。此外，还鉴定了载脂蛋白E在乙醇诱导的细胞毒性中的异构体特异性作用。结果表明，apoE4的加入可降低乙醇诱导的细胞毒性，而apoE2和apoE3的存在均不抑制乙醇的细胞毒性。载脂蛋白E促进乙醇诱导的细胞损伤的确切机制尚不清楚，还需要进一步的研究。然而，本研究表明，乙醇诱导的受体下方第二信使的改变通过基因和细胞内蛋白的表达影响细胞内的转录因子和神经网络的交替结构，从而促进认知障碍的发展。相反，诱导分化为神经元，恢复神经元数量，促进神经网络重构，可用于酒精中毒和阿尔茨海默病的治疗。通过将这些疾病视为脂代谢和神经网络系统功能障碍引起的认知障碍，似乎有可能拓宽我们的治疗策略选择。较少

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