Department of Neurology, MassGeneral Institute of Neurodegenerative Diseases, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129, USA.
Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, 02118, USA.
Sci Rep. 2023 Aug 11;13(1):13075. doi: 10.1038/s41598-023-40402-3.
Patients with Alzheimer's disease (AD) exhibit non-rapid eye movement (NREM) sleep disturbances in addition to memory deficits. Disruption of NREM slow waves occurs early in the disease progression and is recapitulated in transgenic mouse models of beta-amyloidosis. However, the mechanisms underlying slow-wave disruptions remain unknown. Because astrocytes contribute to slow-wave activity, we used multiphoton microscopy and optogenetics to investigate whether they contribute to slow-wave disruptions in APP/PS1 mice. The power but not the frequency of astrocytic calcium transients was reduced in APP/PS1 mice compared to nontransgenic controls. Optogenetic activation of astrocytes at the endogenous frequency of slow waves restored slow-wave power, reduced amyloid deposition, prevented neuronal calcium elevations, and improved memory performance. Our findings revealed malfunction of the astrocytic network driving slow-wave disruptions. Thus, targeting astrocytes to restore circuit activity underlying sleep and memory disruptions in AD could ameliorate disease progression.
阿尔茨海默病（AD）患者除了记忆缺陷外，还表现出非快速眼动（NREM）睡眠障碍。在疾病进展的早期就会出现 NREM 慢波的破坏，并且在β淀粉样蛋白变性的转基因小鼠模型中重现。然而，慢波破坏的机制尚不清楚。因为星形胶质细胞有助于慢波活动，我们使用多光子显微镜和光遗传学来研究它们是否有助于 APP/PS1 小鼠的慢波破坏。与非转基因对照相比，APP/PS1 小鼠星形胶质细胞钙瞬变的幅度而非频率降低。以慢波的内源性频率光遗传学激活星形胶质细胞可恢复慢波幅度，减少淀粉样蛋白沉积，防止神经元钙升高，并改善记忆表现。我们的研究结果揭示了星形胶质细胞网络功能障碍导致慢波破坏。因此，靶向星形胶质细胞以恢复 AD 中睡眠和记忆障碍的电路活动可能会改善疾病进展。
