Sleep restoration by optogenetic targeting of GABAergic neurons reprograms microglia and ameliorates pathological phenotypes in an Alzheimer's disease model.
Sleep restoration by optogenetic targeting of GABAergic neurons reprograms microglia and ameliorates pathological phenotypes in an Alzheimer's disease model.
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DOI：
10.1186/s13024-023-00682-9
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发表时间：
2023-12-01
影响因子：
15.1
通讯作者：
中科院分区：
文献类型：
--
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阿尔茨海默病（AD）患者表现出记忆中断和严重的睡眠障碍，包括深度非快速眼动（NREM）睡眠的中断。慢波活动（SWA）是NREM睡眠的主要恢复特征，对记忆巩固很重要。我们建立了一个小鼠模型，其中GABA能中间神经元可以在APPswe/PS1 dE 9（APP）淀粉样变性的存在下被靶向，APP-GAD-Cre小鼠。脑电图（EEG）/肌电图（EMG）遥测系统用于监测这些动物的睡眠中断。以通道视紫红质-2（ChR 2）为靶点的前皮质GABA能中间神经元的光遗传刺激使我们能够检查GABA能中间神经元在睡眠不足中的作用。我们还研究了光遗传学刺激对淀粉样蛋白斑块、神经元钙以及睡眠依赖性记忆巩固的影响。此外，使用共聚焦显微镜和流式细胞术评估小胶质细胞的形态学特征和功能。最后，我们在光遗传学刺激期间进行睡眠剥夺，以研究睡眠恢复是否是减缓AD进展所必需的。与非转基因（NTG）NTG-GAD-Cre小鼠相比，APP-GAD-Cre小鼠表现出睡眠结构受损，包括NREM睡眠时间减少、δ功率降低和睡眠碎片增加。皮层GABA能中间神经元的光遗传刺激增加了APP-GAD-Cre动物的SWA并挽救了睡眠障碍。此外，它通过减少淀粉样蛋白沉积、使神经元钙稳态正常化和改善记忆功能来减缓AD进展。这些变化伴随着小胶质细胞数量增加和形态转化、吞噬标志物表达升高和小胶质细胞淀粉样蛋白β（Aβ）吞噬活性增强。睡眠是改善APP-GAD-Cre小鼠病理生理表型所必需的。总之，我们的研究表明，GABA能中间神经元的光遗传学靶向挽救睡眠，然后通过增加AD小鼠模型中小胶质细胞对Aβ的清除来改善神经病理学和行为缺陷。在线版本包含补充材料，可通过10.1186/s13024-023-00682-9获得。
Alzheimer’s disease (AD) patients exhibit memory disruptions and profound sleep disturbances, including disruption of deep non-rapid eye movement (NREM) sleep. Slow-wave activity (SWA) is a major restorative feature of NREM sleep and is important for memory consolidation. We generated a mouse model where GABAergic interneurons could be targeted in the presence of APPswe/PS1dE9 (APP) amyloidosis, APP-GAD-Cre mice. An electroencephalography (EEG) / electromyography (EMG) telemetry system was used to monitor sleep disruptions in these animals. Optogenetic stimulation of GABAergic interneurons in the anterior cortex targeted with channelrhodopsin-2 (ChR2) allowed us to examine the role GABAergic interneurons play in sleep deficits. We also examined the effect of optogenetic stimulation on amyloid plaques, neuronal calcium as well as sleep-dependent memory consolidation. In addition, microglial morphological features and functions were assessed using confocal microscopy and flow cytometry. Finally, we performed sleep deprivation during optogenetic stimulation to investigate whether sleep restoration was necessary to slow AD progression. APP-GAD-Cre mice exhibited impairments in sleep architecture including decreased time spent in NREM sleep, decreased delta power, and increased sleep fragmentation compared to nontransgenic (NTG) NTG-GAD-Cre mice. Optogenetic stimulation of cortical GABAergic interneurons increased SWA and rescued sleep impairments in APP-GAD-Cre animals. Furthermore, it slowed AD progression by reducing amyloid deposition, normalizing neuronal calcium homeostasis, and improving memory function. These changes were accompanied by increased numbers and a morphological transformation of microglia, elevated phagocytic marker expression, and enhanced amyloid β (Aβ) phagocytic activity of microglia. Sleep was necessary for amelioration of pathophysiological phenotypes in APP-GAD-Cre mice. In summary, our study shows that optogenetic targeting of GABAergic interneurons rescues sleep, which then ameliorates neuropathological as well as behavioral deficits by increasing clearance of Aβ by microglia in an AD mouse model. The online version contains supplementary material available at 10.1186/s13024-023-00682-9.
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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
影响因子：
4
作者：
Blattner, Margaret S.;Panigrahi, Sunil K.;Lucey, Brendan P.
通讯作者：
Lucey, Brendan P.
影响因子：
4.2
作者：
Deurveilher, Samuel;Golovin, Tatjana;Semba, Kazue
通讯作者：
Semba, Kazue
影响因子：
5.3
作者：
Funk, Chadd M.;Peelman, Kayla;Tononi, Giulio
通讯作者：
Tononi, Giulio
影响因子：
1.1
作者：
Gerashchenko D;Wisor JP;Kilduff TS
通讯作者：
Kilduff TS