An Hoyoung, Cho Mi-Hyang, Kim Dong-Hou, Chung Seockhoon, Yoon Seung-Yong
Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Korea.
National Institute of Dementia, Seongnam, Korea.
J Alzheimers Dis. 2017;58(1):253-261. doi: 10.3233/JAD-170108.
Intracranial accumulation of amyloid-β (Aβ) is a characteristic finding of Alzheimer's disease (AD). It is thought to be the result of Aβ overproduction by neurons and impaired clearance by several systems, including degradation by microglia. Sleep disturbance is now considered a risk factor for AD, but studies focusing on how sleep modulates microglial handling of Aβ have been scarce.
To determine whether phagocytosis and degradation of extracellular Aβ fibrils by BV2 microglial cells were impaired by treatment with orexin-A/B, a major modulator of the sleep-wake cycle, which may mimic sleep deprivation conditions.
BV2 cells were treated with orexin and Aβ for various durations and phagocytic and autophagic processes for degradation of extracellular Aβ were examined.
After treatment with orexin, the formation of actin filaments around Aβ fibrils, which is needed for phagocytosis, was impaired, and phagocytosis regulating molecules such as PI3K, Akt, and p38-MAPK were downregulated in BV2 cells. Orexin also suppressed autophagic flux, through disruption of the autophagosome-lysosome fusion process, resulting in impaired Aβ degradation in BV2 cells.
Our results demonstrate that orexin can hinder clearance of Aβ through the suppression of phagocytosis and autophagic flux in microglia. This is a novel mechanism linking AD and sleep, and suggests that attenuated microglial function, due to sleep deprivation, may increase Aβ accumulation in the brain.
淀粉样β蛋白（Aβ）在颅内的蓄积是阿尔茨海默病（AD）的一个特征性表现。这被认为是神经元Aβ产生过多以及包括小胶质细胞降解在内的多个系统清除功能受损的结果。睡眠障碍现在被认为是AD的一个危险因素，但专注于睡眠如何调节小胶质细胞对Aβ处理的研究却很少。
确定用食欲素A/B（一种睡眠-觉醒周期的主要调节因子，可能模拟睡眠剥夺状态）处理是否会损害BV2小胶质细胞对细胞外Aβ纤维的吞噬和降解。
用食欲素和Aβ对BV2细胞进行不同时长的处理，并检测细胞外Aβ降解的吞噬和自噬过程。
用食欲素处理后，吞噬作用所需的Aβ纤维周围肌动蛋白丝的形成受损，并且BV2细胞中吞噬作用调节分子如PI3K、Akt和p38-MAPK的表达下调。食欲素还通过破坏自噬体-溶酶体融合过程抑制自噬流，导致BV2细胞中Aβ降解受损。
我们的结果表明，食欲素可通过抑制小胶质细胞的吞噬作用和自噬流来阻碍Aβ的清除。这是一种将AD与睡眠联系起来的新机制，提示睡眠剥夺导致的小胶质细胞功能减弱可能会增加大脑中Aβ的蓄积。
