Disruption of the sleep-wake cycle and diurnal fluctuation of β-amyloid in mice with Alzheimer's disease pathology.
Disruption of the sleep-wake cycle and diurnal fluctuation of β-amyloid in mice with Alzheimer's disease pathology.
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DOI：
10.1126/scitranslmed.3004291
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发表时间：
2012-09-05
影响因子：
17.1
通讯作者：
Holtzman DM
中科院分区：
文献类型：
--
作者：
Roh JH;Huang Y;Bero AW;Kasten T;Stewart FR;Bateman RJ;Holtzman DM
β淀粉样蛋白（Aβ）在脑中的聚集在阿尔茨海默病（AD）临床发作前数年就开始发生。在Aβ聚集之前，细胞外可溶性间质液（ISF）Aβ水平（受神经元活动和睡眠-觉醒周期调节）与随后观察到的脑中Aβ沉积量相关。睡眠的数量和质量随着年龄的增长而下降，在AD中更是如此。睡眠质量、睡眠量以及Aβ的昼夜波动如何随年龄和Aβ聚集而变化尚不清楚。我们报道了在Aβ斑块形成前，APPswe/PS 1 δE9小鼠脑内ISF Aβ存在正常的睡眠-觉醒周期和昼夜波动。斑块形成后，睡眠-觉醒周期明显恶化，ISF Aβ的昼夜波动消失。与小鼠一样，早老素突变的年轻成年人脑脊液（CSF）Aβ的昼夜波动也随着Aβ斑块形成而显著减弱。通过Aβ42主动免疫小鼠脑中Aβ沉积物的虚拟消除使睡眠-觉醒周期和ISF Aβ的昼夜波动正常化。这些数据表明，Aβ聚集扰乱了Aβ的睡眠-觉醒周期和昼夜波动。中枢神经系统中Aβ的睡眠-觉醒行为和昼夜波动似乎分别是Aβ相关病理学的功能和生化标志物，应在症状发作前后以及治疗反应中对人类进行诊断探索。
Aggregation of amyloid-β (Aβ) in the brain begins to occur years prior to the clinical onset of Alzheimer’s disease (AD). Prior to Aβ aggregation, levels of extracellular, soluble interstitial fluid (ISF) Aβ, which are regulated by neuronal activity and the sleep-wake cycle, correlate with the amount of Aβ deposition in the brain seen later. The amount and quality of sleep declines with aging and to a greater extent in AD. How sleep quality amount as well as the diurnal fluctuation in Aβ change with age and Aβ aggregation are not well understood. We report that a normal sleep-wake cycle and diurnal fluctuation of ISF Aβ is present in the brain of APPswe/PS1δE9 mice before Aβ plaque formation. Following plaque formation, the sleep-wake cycle markedly deteriorated and diurnal fluctuation of ISF Aβ dissipated. As in mice, diurnal fluctuation of cerebrospinal fluid (CSF) Aβ in young adult humans with presenilin mutations was also markedly attenuated with Aβ plaque formation. Virtual elimination of Aβ deposits in the mouse brain by active immunization with Aβ42 normalized the sleep-wake cycle and the diurnal fluctuation of ISF Aβ. These data suggest that Aβ aggregation disrupts the sleep-wake cycle and diurnal fluctuation of Aβ. Sleep-wake behavior and diurnal fluctuation of Aβ in the central nervous system appear to be functional and biochemical markers respectively of Aβ-associated pathology that should be explored in humans diagnostically prior to and following symptom onset and in response to treatment.
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DOI：
10.1126/science.1180962
发表时间：
2009-11-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kang JE;Lim MM;Bateman RJ;Lee JJ;Smyth LP;Cirrito JR;Fujiki N;Nishino S;Holtzman DM
通讯作者：
Holtzman DM
DOI：
10.1523/jneurosci.5845-11.2012
发表时间：
2012-03-28
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Bero AW;Bauer AQ;Stewart FR;White BR;Cirrito JR;Raichle ME;Culver JP;Holtzman DM
通讯作者：
Holtzman DM
DOI：
10.1126/science.1169096
发表时间：
2009-02-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kuchibhotla KV;Lattarulo CR;Hyman BT;Bacskai BJ
通讯作者：
Bacskai BJ
影响因子：
16.2
作者：
Kamenetz, F;Tomita, T;Malinow, R
通讯作者：
Malinow, R
影响因子：
82.9
作者：
Jucker, Mathias
通讯作者：
Jucker, Mathias