Department of Neurology, University of Wisconsin-Madison, Madison, WI.
Sleep. 2020 Nov 12;43(11). doi: 10.1093/sleep/zsaa087.
Accumulating evidence suggests a strong association between sleep, amyloid-beta (Aβ) deposition, and Alzheimer's disease (AD). We sought to determine if (1) deficits in rest-activity rhythms and sleep are significant phenotypes in J20 AD mice, (2) metabotropic glutamate receptor 5 inhibitors (mGluR5) could rescue deficits in rest-activity rhythms and sleep, and (3) Aβ levels are responsive to treatment with mGluR5 inhibitors.
Diurnal rest-activity levels were measured by actigraphy and sleep-wake patterns by electroencephalography, while animals were chronically treated with mGluR5 inhibitors. Behavioral tests were performed, and Aβ levels measured in brain lysates.
J20 mice exhibited a 4.5-h delay in the acrophase of activity levels compared to wild-type littermates and spent less time in rapid eye movement (REM) sleep during the second half of the light period. J20 mice also exhibited decreased non-rapid eye movement (NREM) delta power but increased NREM sigma power. The mGluR5 inhibitor CTEP rescued the REM sleep deficit and improved NREM delta and sigma power but did not correct rest-activity rhythms. No statistically significant differences were observed in Aβ levels, rotarod performance, or the passive avoidance task following chronic mGluR5 inhibitor treatment.
J20 mice have disruptions in rest-activity rhythms and reduced homeostatic sleep pressure (reduced NREM delta power). NREM delta power was increased following treatment with a mGluR5 inhibitor. Drug bioavailability was poor. Further work is necessary to determine if mGluR5 is a viable target for treating sleep phenotypes in AD.
越来越多的证据表明，睡眠、淀粉样蛋白-β（Aβ）沉积与阿尔茨海默病（AD）之间存在很强的关联性。我们试图确定：（1）J20 AD 小鼠是否存在休息-活动节律和睡眠缺陷等显著表型；（2）代谢型谷氨酸受体 5 抑制剂（mGluR5）能否改善休息-活动节律和睡眠缺陷；（3）Aβ 水平对 mGluR5 抑制剂的治疗是否有反应。
通过活动记录仪测量昼夜休息-活动水平，通过脑电图测量睡眠-觉醒模式，同时对动物进行慢性 mGluR5 抑制剂治疗。进行行为测试，并测量脑匀浆中的 Aβ 水平。
与野生型同窝仔相比，J20 小鼠的活动水平峰值延迟了 4.5 小时，在光照期的后半段 REM 睡眠时间减少。J20 小鼠还表现出非快速眼动（NREM）δ波功率降低，而 NREMσ波功率增加。mGluR5 抑制剂 CTEP 可挽救 REM 睡眠缺陷，并改善 NREMδ和σ波功率，但不能纠正休息-活动节律。慢性 mGluR5 抑制剂治疗后，Aβ 水平、转棒测试表现或被动回避任务均未观察到统计学上的显著差异。
J20 小鼠存在休息-活动节律紊乱和稳态睡眠压力降低（NREMδ波功率降低）。mGluR5 抑制剂治疗后，NREMδ波功率增加。药物生物利用度较差。需要进一步研究确定 mGluR5 是否是治疗 AD 睡眠表型的可行靶点。
