Alzheimer's Disease and Methanol Toxicity (Part 1): Chronic Methanol Feeding Led to Memory Impairments and Tau Hyperphosphorylation in Mice
Alzheimer's Disease and Methanol Toxicity (Part 1): Chronic Methanol Feeding Led to Memory Impairments and Tau Hyperphosphorylation in Mice
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阿尔茨海默病和甲醇毒性（第 1 部分）：长期喂食甲醇会导致小鼠记忆受损和 Tau 蛋白过度磷酸化
DOI：
10.3233/jad-131529
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发表时间：
2014-01-01
影响因子：
4
通讯作者：
He, Rongqiao
中科院分区：
文献类型：
--
作者：
Yang, Meifeng;Lu, Jing;He, Rongqiao
尽管众所周知，甲醇中毒会导致急性神经后遗症导致失明或死亡，但有了新的动力来研究甲醇暴露的慢性影响。这些包括最近建立的甲醛，一种甲醇代谢物，和阿尔茨海默病(AD)病理之间的联系。在目前的研究中，小鼠被喂以甲醇来重新观察甲醇毒性的慢性影响，特别是当它与AD进展有关时。三组小鼠(n=9)被给予水作为对照，或给予浓度为2%或3.8%的甲醇溶液，持续6周。研究发现，甲醇喂养的小鼠在Y迷宫和嗅觉记忆范式中的空间识别和嗅觉记忆能力受损。对小鼠大脑的免疫组织化学分析发现，在甲醇喂养组中，海马区神经元tau磷酸化水平增加，海马区CA1区神经元(类似于10%的神经元呈现染色质凝聚)细胞凋亡标志物增加。另外两项在小鼠胚胎大脑皮层神经元和小鼠神经母细胞瘤N2a细胞的体外实验发现，甲醛，而不是甲醇或甲醇最终产物甲酸，可以诱导微管解体和tau蛋白过度磷酸化。行为测试和免疫组织化学分析的结果表明，甲醇喂养的小鼠出现了部分AD样症状。体外实验表明，甲醛最有可能是与小鼠海马tau磷酸化和随后的记忆受损有关的甲醇毒性的有害成分。这些发现增加了越来越多的证据，将甲醛与AD病理联系起来。
Although methanol toxicity is well known for acute neurological sequelae leading to blindness or death, there is a new impetus to investigate the chronic effects of methanol exposure. These include a recently established link between formaldehyde, a methanol metabolite, and Alzheimer's disease (AD) pathology. In the present study, mice were fed with methanol to revisit the chronic effects of methanol toxicity, especially as it pertains to AD progression. Three groups of mice (n = 9) were given either water as a control or a methanol solution (concentrations of 2% or 3.8%) over a 6-week period. The methanol-fed mice were found to have impaired spatial recognition and olfactory memory in Y-maze and olfactory memory paradigms. Immunohistochemical analysis of the mouse brains found increased neuronal tau phosphorylation in the hippocampus and an increased cellular apoptotic marker in hippocampal CA1 neurons (similar to 10% of neurons displayed chromatin condensation) in the methanol-fed groups. Two additional in vitro experiments in mouse embryonic cerebral cortex neurons and mouse neuroblastoma N2a cells found that formaldehyde, but not methanol or the methanol end product formic acid, induced microtubule disintegration and tau protein hyperphosphorylation. The findings of the behavioral tests and immunohistochemical analysis suggested that the methanol-fed mice presented with partial AD-like symptoms. The in vitro experiments suggested that formaldehyde was most likely the detrimental component of methanol toxicity related to hippocampal tau phosphorylation and the subsequent impaired memory in the mice. These findings add to a growing body of evidence that links formaldehyde to AD pathology.