Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, 4202 E. Fowler Ave., ISA 2015, Tampa, FL 33620, USA.
Neuropharmacology. 2012 Dec;63(8):1368-79. doi: 10.1016/j.neuropharm.2012.08.018. Epub 2012 Sep 1.
Caffeine and melatonin have been shown to protect the Swedish mutant amyloid precursor protein (APP(sw)) transgenic mouse model of Alzheimer's disease from cognitive dysfunction. But their mechanisms of action remain incompletely understood. These Alzheimer's mice have extensive mitochondrial dysfunction, which likely contributes to their cognitive decline. To further explore the mechanism through which caffeine and melatonin protect cognitive function in these mice, we monitored the function of isolated mitochondria from APP(sw) mice treated with caffeine, melatonin, or both in their drinking water for one month. Melatonin treatment yielded a near complete restoration of mitochondrial function in assays of respiratory rate, membrane potential, reactive oxygen species production, and ATP levels. Caffeine treatment by itself yielded a small increase in mitochondrial function. However, caffeine largely blocked the large enhancement of mitochondrial function provided by melatonin. Studies with N2a neuroblastoma cells stably expressing APP(sw) showed that specific inhibition of cAMP-dependent phosphodiesterase (PDE) 4 or cGMP-dependent PDE5 also blocked melatonin protection of mitochondrial function, but A(2a) and A₁ adenosine receptor antagonists were without effect. Melatonin or caffeine at the concentrations used to modulate mitochondrial function in the cells had no effect on cAMP-dependent PDE activity or cellular cAMP or cGMP levels. Therefore, caffeine and increased cyclic nucleotide levels likely block melatonin signaling to mitochondria by independent mechanisms that do not involve adenosine receptor antagonism. The results of this study indicate that melatonin restores mitochondrial function much more potently than caffeine in APP(sw) transgenic mouse and cell models of Alzheimer's disease.
咖啡因和褪黑素已被证明可保护瑞典突变淀粉样前体蛋白（APP（sw））转基因阿尔茨海默病小鼠模型免受认知功能障碍的影响。但其作用机制仍不完全清楚。这些阿尔茨海默病小鼠有广泛的线粒体功能障碍，这可能导致它们认知能力下降。为了进一步探索咖啡因和褪黑素保护这些小鼠认知功能的机制，我们监测了用咖啡因、褪黑素或两者同时处理饮用水一个月的 APP（sw）小鼠分离的线粒体的功能。褪黑素治疗使呼吸率、膜电位、活性氧物质产生和 ATP 水平的测定中的线粒体功能几乎完全恢复。咖啡因治疗本身可略微增加线粒体功能。然而，咖啡因在很大程度上阻止了褪黑素提供的线粒体功能的大幅增强。用稳定表达 APP（sw）的 N2a 神经母细胞瘤细胞进行的研究表明，特异性抑制环磷酸腺苷（cAMP）依赖性磷酸二酯酶（PDE）4 或环鸟苷酸（cGMP）依赖性 PDE5 也阻断了褪黑素对线粒体功能的保护，但 A₂a 和 A₁ 腺苷受体拮抗剂没有效果。在用于调节细胞中线粒体功能的浓度下，褪黑素或咖啡因对 cAMP 依赖性 PDE 活性或细胞内 cAMP 或 cGMP 水平没有影响。因此，咖啡因和增加的环核苷酸水平可能通过不涉及腺苷受体拮抗的独立机制阻断褪黑素对线粒体的信号传递。本研究的结果表明，褪黑素在 APP（sw）转基因小鼠和阿尔茨海默病细胞模型中比咖啡因更有效地恢复线粒体功能。
