STM:睡眠觉醒周期和Aβ昼夜变化在阿尔茨海默氏病的意义

在阿尔茨海默氏病（AD）临床发作之前，大脑中的β-淀粉样蛋白（Aβ）就已经开始聚集。在Aβ聚集发生以前，大脑组织间液（ISF）的细胞外可溶性Aβ浓度（该浓度受神经活动和睡眠 - 觉醒周期所调节），与大脑中Aβ的沉积量相关。

随着衰老过程的不断进展，人类的睡眠数量和质量逐渐下降。这种下降在AD患者表现得更明显。但是，睡眠质量以及Aβ的昼夜波动如何随着年龄的增长和Aβ聚集变化，还不是很清楚。

本研究发现，在APPswe/PS1δE9小鼠AD模型中，Aβ斑块形成之前，存在一个正常的睡眠 - 觉醒周期。同时，ISF Aβ在大脑中浓度呈现昼夜波动。斑块形成后，睡眠 - 觉醒周期显著恶化，ISF Aβ的昼夜变化也渐渐消散。

与小鼠类似，脑脊液Aβ浓度在早老素基因（presenilin）突变的年轻成年人中的昼夜波动也在Aβ斑块形成后明显减弱。

这些数据表明，Aβ聚集扰乱睡眠 - 觉醒周期和Aβ浓度的昼夜变化。睡眠 - 觉醒行为和在中枢神经系统中的Aβ昼夜波动可能分别是反映Aβ-相关病理变化的功能和生化指标。

doi:10.1016/j.cell.2011.10.017
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Disruption of the Sleep-Wake Cycle and Diurnal Fluctuation of β-Amyloid in Mice with Alzheimer’s Disease Pathology

Jee Hoon Roh1,2,3, Yafei Huang1, Adam W. Bero1,2,3, Tom Kasten1, Floy R. Stewart1,2,3, Randall J. Bateman1,2,3 and David M. Holtzman

Aggregation of β-amyloid (Aβ) in the brain begins to occur years before the clinical onset of Alzheimer’s disease (AD). Before Aβ aggregation, concentrations of extracellular soluble Aβ in the interstitial fluid (ISF) space of the brain, 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 decline with normal aging and to a greater extent in AD patients. How sleep quality as well as the diurnal fluctuation in Aβ change with age and Aβ aggregation is not well understood. We report a normal sleep-wake cycle and diurnal fluctuation in ISF Aβ in the brain of the APPswe/PS1δE9 mouse model of AD before Aβ plaque formation. After plaque formation, the sleep-wake cycle markedly deteriorated and diurnal fluctuation of ISF Aβ dissipated. As in mice, diurnal fluctuation of cerebrospinal fluid Aβ in young adult humans with presenilin mutations was also markedly attenuated after 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 may be functional and biochemical indicators, respectively, of Aβ-associated pathology.