Sleep interacts with aβ to modulate intrinsic neuronal excitability.
Sleep interacts with aβ to modulate intrinsic neuronal excitability.
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DOI：
10.1016/j.cub.2015.01.016
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发表时间：
2015-03-16
期刊：
影响因子：
9.2
通讯作者：
Wu, Mark N.
中科院分区：
文献类型：
--
作者：
Tabuchi, Masashi;Lone, Shahnaz R.;Liu, Sha;Liu, Qili;Zhang, Julia;Spira, Adam P.;Wu, Mark N.
新出现的数据表明，睡眠和阿尔茨海默病(AD)之间存在重要关系，但睡眠不足如何促进AD的发展仍不清楚。在这里，使用果蝇的AD模型，我们提供的证据表明，神经元兴奋性的变化是睡眠不足在AD发病机制中作用的基础。β-淀粉样蛋白(A-β)的积聚会导致睡眠减少和零碎，而长期睡眠剥夺会增加A-β的负担。此外，增加睡眠可以减少Aβ的沉积。增加神经元兴奋性表现为减少睡眠对Aβ的影响，减少神经元活动可阻断睡眠剥夺引起的Aβ蓄积增加。在单个神经元水平上，我们发现慢性睡眠剥夺以及Aβ的表达增强了神经元的内在兴奋性。重要的是，这些数据揭示了睡眠不足加剧了Aβ诱导的过度兴奋性，并提示特定K+电流的缺陷是睡眠缺失和Aβ表达引起的过度兴奋性的基础。最后，我们发现，给表达β的果蝇喂食抗癫痫药物左乙拉西坦可以抑制神经元的兴奋性，并显著延长它们的寿命。我们的发现直接将睡眠不足与神经元兴奋性和Aβ蓄积的变化联系在一起，进一步表明神经元的过度兴奋性是Aβ毒性的重要中介。综上所述，这些数据为正反馈环路提供了一个机制框架，睡眠缺失和神经元兴奋加速了Aβ的积累，这是AD发展中的一个关键致病步骤。
Emerging data suggest an important relationship between sleep and Alzheimer’s Disease (AD), but how poor sleep promotes the development of AD remains unclear. Here, using a Drosophila model of AD, we provide evidence suggesting that changes in neuronal excitability underlie the effects of sleep loss on AD pathogenesis. β-amyloid (Aβ) accumulation leads to reduced and fragmented sleep, while chronic sleep deprivation increases Aβ burden. Moreover, enhancing sleep reduces Aβ deposition. Increasing neuronal excitability phenocopies the effects of reducing sleep on Aβ, and decreasing neuronal activity blocks the elevated Aβ accumulation induced by sleep deprivation. At the single neuron level, we find that chronic sleep deprivation, as well as Aβ expression, enhances intrinsic neuronal excitability. Importantly, these data reveal that sleep loss exacerbates Aβ–induced hyperexcitability and suggest that defects in specific K+ currents underlie the hyperexcitability caused by sleep loss and Aβ expression. Finally, we show that feeding levetiracetam, an anti-epileptic medication, to Aβ-expressing flies suppresses neuronal excitability and significantly prolongs their lifespan. Our findings directly link sleep loss to changes in neuronal excitability and Aβ accumulation and further suggest that neuronal hyperexcitability is an important mediator of Aβ toxicity. Taken together, these data provide a mechanistic framework for a positive feedback loop, whereby sleep loss and neuronal excitation accelerate the accumulation of Aβ, a key pathogenic step in the development of AD.
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DOI：
10.1126/science.1202839
发表时间：
2011-06-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bushey D;Tononi G;Cirelli C
通讯作者：
Cirelli C
DOI：
10.1073/pnas.1206171109
发表时间：
2012-05-29
影响因子：
11.1
作者：
Busche, Marc Aurel;Chen, Xiaowei;Konnerth, Arthur
通讯作者：
Konnerth, Arthur
影响因子：
2.5
作者：
Espinosa, F;Marks, G;Joho, RH
通讯作者：
Joho, RH
影响因子：
34.7
作者：
Cirelli, Chiara
通讯作者：
Cirelli, Chiara
影响因子：
18.2
作者：
Allada R;Chung BY
通讯作者：
Chung BY