Melatonin treatment restores mitochondrial function in Alzheimer's mice: a mitochondrial protective role of melatonin membrane receptor signaling
Melatonin treatment restores mitochondrial function in Alzheimer's mice: a mitochondrial protective role of melatonin membrane receptor signaling
复制标题
DOI：
10.1111/j.1600-079x.2011.00864.x
复制
发表时间：
2011-08-01
影响因子：
10.3
通讯作者：
Bradshaw, Patrick C.
中科院分区：
文献类型：
--
作者：
Dragicevic, Natasa;Copes, Neil;Bradshaw, Patrick C.
线粒体功能障碍是阿尔茨海默病(AD)的一个标志，并在家族性AD的突变淀粉样前体蛋白(APP)转基因小鼠模型中观察到。褪黑素是一种有效的抗氧化剂，可以防止阿尔茨海默病β-淀粉样多肽的毒性聚集，长期服用可以保护APP转基因小鼠的认知障碍。为研究褪黑素对AD模型小鼠脑线粒体功能的影响，用褪黑素对APP/PS1转基因小鼠进行为期1个月的治疗。对分离的小鼠脑线粒体的分析表明，褪黑素治疗使不同脑区的线粒体抗体水平降低了两到四倍。伴随而来的是线粒体呼吸频率、膜电位和分离的海马区、皮质或纹状体线粒体的ATP水平几乎完全恢复。当未处理的幼鼠的分离线粒体被给予褪黑素时，观察到呼吸频率略有增加。在衰老小鼠的线粒体中没有观察到这样的影响。在培养的表达APP的神经母细胞瘤细胞中，褪黑素或结构上相关的化合物吲哚-3-丙酸或N(1)-乙酰基-N(2)-甲酰基-5-甲氧基犬尿胺可恢复线粒体功能。褪黑素受体拮抗剂部分阻断了这种恢复，这表明褪黑素受体信号是发挥全部作用所必需的。因此，刺激褪黑素受体信号转导的治疗可能有利于AD患者线粒体功能的恢复，而线粒体功能的保护可能是褪黑素长期治疗延缓AD小鼠认知功能障碍的重要机制。
Mitochondrial dysfunction is a hallmark of Alzheimer's disease (AD) and is observed in mutant amyloid precursor protein (APP) transgenic mouse models of familial AD. Melatonin is a potent antioxidant, can prevent toxic aggregation of Alzheimer's beta-amyloid (Ab) peptide and, when taken long term, can protect against cognitive deficits in APP transgenic mice. To study the effects of melatonin on brain mitochondrial function in an AD model, APP/PS1 transgenic mice were treated for 1 month with melatonin. Analysis of isolated brain mitochondria from mice indicated that melatonin treatment decreased mitochondrial Ab levels by two-to fourfold in different brain regions. This was accompanied by a near complete restoration of mitochondrial respiratory rates, membrane potential, and ATP levels in isolated mitochondria from the hippocampus, cortex, or striatum. When isolated mitochondria from untreated young mice were given melatonin, a slight increase in respiratory rate was observed. No such effect was observed in mitochondria from aged mice. In APP-expressing neuroblastoma cells in culture, mitochondrial function was restored by melatonin or by the structurally related compounds indole-3-propionic acid or N(1)-acetyl-N(2)-formyl-5-methoxykynuramine. This restoration was partially blocked by melatonin receptor antagonists indicating melatonin receptor signaling is required for the full effect. Therefore, treatments that stimulate melatonin receptor signaling may be beneficial for restoring mitochondrial function in AD, and preservation of mitochondrial function may an important mechanism by which long term melatonin treatment delays cognitive dysfunction in AD mice.