老年性痴呆发病过程中内源性甲醛慢性损伤机制  

Formaldehyde-mediated Chronic Damage May Be Related to Sporadic Neurodegeneration

作　　者：李芳序[1] 卢静[1] 许亚杰[1] 童志前[1] 聂春来[1] 赫荣乔[1] 

机构地区：[1]脑与认知科学国家重点实验室,中国科学院生物物理研究所,北京100101

出　　处：《生物化学与生物物理进展》2008年第4期393-400,共8页Progress In Biochemistry and Biophysics

基　　金：国家自然科学基金(90206041,30570536);国家重点基础研究发展计划(973)(2006CB500703);中国科学院创新经费(KSCX2-YW-R-119)资助项目~~

摘　　要：通过原子力显微镜、荧光标记、Congo染色等方法,观察到低浓度甲醛可以诱导人类神经Tau蛋白错误折叠并形成具有细胞毒性的似球状聚积物;气相色谱和液相色谱等分析结果表明,神经鞘磷脂N-Acyl-4-sphingoine-1-phosphocholine(myelin)的过氧化能够产生甲醛分子;脂质过氧化的代谢产物丙二醛(malondialdehyde)在修饰蛋白质(BSA)的过程中,亦可产生甲醛分子.以上结果为内源性甲醛的产生揭示了新的途径.值得注意的是,在生理条件下,血液中内源性甲醛的水平维持在一个动态平衡((0.087±0.004)mmol/L),与体外培养神经细胞时甲醛产生毒性的浓度(～0.1mmol/L)十分接近,甚至已经达到产生一定细胞毒性的水平.随着机体的衰老,内源性甲醛的调节机能下降,在氧化应激等相关因素的诱导作用下,内源性甲醛浓度可能升高,对中枢神经系统一定部位的神经细胞造成慢性损伤,这可能是散发性老年痴呆发病的机制之一.Formaldehyde is directly toxic to cells and its intermediate metabolite formic acid leads to acidosis in microenvironment in vivo. According to recent literatures, endogenous formaldehyde production is related to several metabolic pathways such as amine oxidation （catalyzed by semicarbazide-sensitive amine oxidase, SSAO）, methylation and demethylation. Under oxidation stress and energy metabolic imbalance, formaldehyde markedly increases in human circulation. Here, the authors found that formaldehyde is released from the reaction of malondialdehyde with a protein （BSA） in which protein side chains such as amino groups are chemically modified. Moreover, formaldehyde is also produced from the sphingomyelin solution in the presence of hydrogen peroxide as the myelin peroxidation occurs. Formaldehyde at low concentration induces neuronal Tau aggregation, resulting in formation of globular like aggregates which are toxic to SH-SY5Y cells, HEK-293 cells and hippocampus neurons in the primary culture. According to Chen et al. （2006）, endogenous aldehydes are related to beta-amyloid misfolding, oligomerization and fibrillogenesis. Furthermore, formaldehyde is able to react with some neurotransmitters and thus impairs their structures and functions. Under physiological conditions, the human blood formaldehyde is dynamically kept approximately （0.087±0.004） mmol/L. Notably, this concentration is close to the half-lethal dose of formaldehyde （0.10～0.12 mmol/L） to neural cells in the in vitro cell culture such as SH-SY5Y cells. Furthermore, cell growth can be partially affected and inhibited in the presence of formaldehyde at （0.087± 0.004） mmol/L during the in vitro culture. This suggests that human body needs a strong degradation system to remove endogenous formaldehyde. As shown in clinical trials, the formaldehyde level in urine of Alzheimer＇s patients was markedly higher than the control subjects. The urine formaldehyde level was shown to be related to the cognitive impairment. Therefore, t

关 键 词：内源性甲醛 脂质过氧化 丙二醛 能量代谢失衡 散发性老年痴呆 甲醛慢性损伤 

分 类 号：Q5[生物学—生物化学] R74[医药卫生—神经病学与精神病学]